ACS Publications. Most Trusted. Most Cited. Most Read
Natural Compound from Olive Oil Inhibits S100A9 Amyloid Formation and Cytotoxicity: Implications for Preventing Alzheimer’s Disease
More

OR SEARCH CITATIONS

My Activity
Publications

Figure 1Loading Img
Download Hi-Res ImageDownload to MS-PowerPointCite This:ACS Chem. Neurosci. 2021, 12, 11, 1905-1918
  • Open Access
Research Article

Natural Compound from Olive Oil Inhibits S100A9 Amyloid Formation and Cytotoxicity: Implications for Preventing Alzheimer’s Disease
Click to copy article linkArticle link copied!

  • Manuela Leri
    Manuela Leri
    Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50134 Florence, Italy
    Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, 50139 Florence, Italy
    More by Manuela Leri
  • Himanshu Chaudhary
    Himanshu Chaudhary
    Department of Medical Biochemistry and Biophysics, Umeå University, 90187 Umeå, Sweden
    More by Himanshu Chaudhary
  • Igor A. Iashchishyn
    Igor A. Iashchishyn
    Department of Medical Biochemistry and Biophysics, Umeå University, 90187 Umeå, Sweden
    More by Igor A. Iashchishyn
    Orcidhttps://orcid.org/0000-0002-1691-9025
  • Jonathan Pansieri
    Jonathan Pansieri
    Department of Medical Biochemistry and Biophysics, Umeå University, 90187 Umeå, Sweden
    More by Jonathan Pansieri
    Orcidhttps://orcid.org/0000-0001-8918-9943
  • Željko M. Svedružić
    Željko M. Svedružić
    Department of Biotechnology, University of Rijeka, HR 51000 Rijeka, Croatia
    More by Željko M. Svedružić
    Orcidhttps://orcid.org/0000-0002-0736-6182
  • Silvia Gómez Alcalde
    Silvia Gómez Alcalde
    Department of Medical Biochemistry and Biophysics, Umeå University, 90187 Umeå, Sweden
    More by Silvia Gómez Alcalde
  • Greta Musteikyte
    Greta Musteikyte
    Institute of Biotechnology, Life Sciences Center, Vilnius University, LT-10257 Vilnius, Lithuania
    More by Greta Musteikyte
  • Vytautas Smirnovas
    Vytautas Smirnovas
    Institute of Biotechnology, Life Sciences Center, Vilnius University, LT-10257 Vilnius, Lithuania
    More by Vytautas Smirnovas
  • Massimo Stefani
    Massimo Stefani
    Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50134 Florence, Italy
    More by Massimo Stefani
  • Monica Bucciantini*
    Monica Bucciantini
    Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50134 Florence, Italy
    *Email: [email protected]
    More by Monica Bucciantini
  • Ludmilla A. Morozova-Roche*
    Ludmilla A. Morozova-Roche
    Department of Medical Biochemistry and Biophysics, Umeå University, 90187 Umeå, Sweden
    *Phone: +46736205283, +46907865283. Email: [email protected]
    More by Ludmilla A. Morozova-Roche
    Orcidhttps://orcid.org/0000-0001-5886-2023
Open PDFSupporting Information (1)

ACS Chemical Neuroscience

Cite this: ACS Chem. Neurosci. 2021, 12, 11, 1905–1918
Click to copy citationCitation copied!
https://doi.org/10.1021/acschemneuro.0c00828
Published May 12, 2021

Copyright © 2021 The Authors. Published by American Chemical Society. This publication is licensed under

CC-BY 4.0 .

Abstract

Click to copy section linkSection link copied!
High Resolution Image
Download MS PowerPoint Slide

Polyphenolic compounds in the Mediterranean diet have received increasing attention due to their protective properties in amyloid neurodegenerative and many other diseases. Here, we have demonstrated for the first time that polyphenol oleuropein aglycone (OleA), which is the most abundant compound in olive oil, has multiple potencies for the inhibition of amyloid self-assembly of pro-inflammatory protein S100A9 and the mitigation of the damaging effect of its amyloids on neuroblastoma SH-SY5Y cells. OleA directly interacts with both native and fibrillar S100A9 as shown by intrinsic fluorescence and molecular dynamic simulation. OleA prevents S100A9 amyloid oligomerization as shown using amyloid oligomer-specific antibodies and cross-β-sheet formation detected by circular dichroism. It decreases the length of amyloid fibrils measured by atomic force microscopy (AFM) as well as reduces the effective rate of amyloid growth and the overall amyloid load as derived from the kinetic analysis of amyloid formation. OleA disintegrates already preformed fibrils of S100A9, converting them into nonfibrillar and nontoxic aggregates as revealed by amyloid thioflavin-T dye binding, AFM, and cytotoxicity assays. At the cellular level, OleA targets S100A9 amyloids already at the membranes as shown by immunofluorescence and fluorescence resonance energy transfer, significantly reducing the amyloid accumulation in GM1 ganglioside containing membrane rafts. OleA increases overall cell viability when neuroblastoma cells are subjected to the amyloid load and alleviates amyloid-induced intracellular rise of reactive oxidative species and free Ca2+. Since S100A9 is both a pro-inflammatory and amyloidogenic protein, OleA may effectively mitigate the pathological consequences of the S100A9-dependent amyloid-neuroinflammatory cascade as well as provide protection from neurodegeneration, if used within the Mediterranean diet as a potential preventive measure.

This publication is licensed under

CC-BY 4.0 .
  • cc licence
  • by licence
Copyright © 2021 The Authors. Published by American Chemical Society

Subjects

what are subjects

Keywords

what are keywords

Note Added after ASAP Publication

This paper was published on May 12, 2021, with an author’s name misspelled. The corrected version was reposted on May 13, 2021.

Introduction

Click to copy section linkSection link copied!
Alzheimer’s disease (AD) and Parkinson’s disease (PD) as well as other amyloid-related neurodegenerative ailments are age-related multifaceted pathological conditions in which a broad range of events lead to the impairment of brain activity with cognitive disability as the main clinical hallmark. The majority of nonfamilial neurodegenerative diseases are characterized by gradual development, usually spanning many years, and with the appearance of their clinical signs at the later stage, when cell decay is obvious and cannot be reversed. In spite of numerous efforts to understand the specific molecular and cellular mechanisms underlying AD and PD pathologies and their potential triggers, effective disease-modifying treatments still remain elusive. Therefore, the delay of the disease onset by a healthy lifestyle and diet remains the best strategy.
Neuroinflammation and amyloid burden are two characteristic pathologies of AD, PD, and other neurodegenerative disorders. (1−3) The amyloid cascade is linked to the failure of polypeptides to adopt and retain their native structure and function, leading to their conversion into toxic amyloid oligomers and insoluble amyloid deposits. The amyloid conversion impairs the physiological function of native polypeptide and leads to a gain in amyloid cytotoxicity. The latter further interferes with signaling pathways and cell homeostasis, including redox equilibrium, free Ca2+ level, and proteostasis. (4) Distinct polypeptides are associated with particular human disorders, notably the Aβ peptide with AD and α-synuclein with PD; however, the growth and deposition of amyloids are shared features of numerous amyloid neurodegenerative diseases. (2) Previously, neuroinflammation was viewed as a reaction to the degeneration process; however, presently, it is known that neuroinflammation may play a central role in triggering and promoting neurodegeneration, since inflammation processes in the brain environment may promote amyloid self-assembly. In AD and PD, the affected tissues in the brain display a range of damaging responses, including substantial activation of microglia and an increase in the level of inflammatory cytokines, which sustain inflammation and exacerbate neurodegeneration. (5−8)
Recently, we have reported that the pro-inflammatory and amyloidogenic protein S100A9 is a major contributor to both the amyloid and neuroinflammatory cascades in AD, PD, and traumatic brain injury; importantly, traumatic brain injury may play a role of the precursor state for numerous neurodegenerative conditions. Thus, S100A9 may bridge the amyloid self-assembly and inflammation into the distinctive and common neurodegenerative disease feature: the amyloid-neuroinflammatory cascade. (9−11) S100A9 has been described as an alarmin implicated in numerous signaling pathways in cancers and inflammation-related diseases. (12,13) The high level of S100A9 expression was also observed in malaria, (14) ischemia, (15) obesity, (16) and cardiovascular disease. (17) The S100A9 mRNA was found to be abundant in numerous aged mammalian organs, also involving the central nervous system; consequently, it was suggested that an age-associated inflammation is implicated and persists due to continued S100A9 production. (18)
Previously, we have found that S100A9 is a very amyloidogenic protein; i.e., in vitro S100A9 aggregates easily under a physiological environment, and its self-assembly is well-defined by a nucleation-autocatalytic growth model. (19) The S100A9 self-assembly into amyloids results in acquired cytotoxicity, exceeding the levels of Aβ peptide amyloid cytotoxicity in AD (11) and α-synuclein amyloid cytotoxicity in PD. (10) This implies that the increased level of S100A9 persisting during inflammation may provoke its amyloid self-assembly, deposition, and tissue damage, which we observed in neurodegenerative diseases, (10,11) in the aged prostate, (20) and in the cell model for S100A8 and S100A9 amyloid accumulation. (21) Indeed, in AD, S100A9 coassembles with Aβ, leading to intracellular amyloid accumulation and extracellular amyloid plaque growth; (11) in PD, S100A9 coaggregates with α-synuclein, which is manifested in Lewy body development, (10) while in traumatic brain injury, S100A9 protein deposits into numerous precursor plaques. (9) We have found also that S100A9 levels in CSF of AD and mild cognitive impairment match those of Aβ, further confirming its involvement in the amyloid-neuroinflammatory cascade even at the disease preclinical and mild stages. (22) Thus, S100A9 may easily aggregate by itself or coaggregate with various other proteins and peptides involved in the amyloid-related diseases and may be considered as an object for therapeutic treatments. This is particularly important, since the whole amyloid cascade may be potentially affected or reversed by targeting the amyloid self-assembly of its single component, such as the S100A9 protein.
Despite significant efforts over the past decades, there are still no drugs available to modify amyloid neurodegenerative disease progression, and despite many compounds being characterized by promising amyloid inhibiting properties in in vitro experiments, they failed in the clinical trials. Many low molecular weight substances, peptides, and various antibodies were examined as prospective amyloid modifiers, yet potent, natural compounds without significant side effects are still needed for effective therapeutic treatments.
Numerous clinical trials and population analysis support the notion that the Mediterranean diet correlates with a decreased occurrence of age-related ailments, such as neurodegenerative disorders. (23−25) The most important characteristic of the Mediterranean diet is the high consumption of natural plant phenols (24) found in many plant products, such as extra virgin olive oil (EVOO). Oleuropein is a secoiridoid glycoside containing phenylpropanoid alcohol, which can be produced from the biosynthesis of mevalonic acid. After the maturation process and extraction of EVOO, as a result of the β-glucosidase enzyme activity, this secoiridoid is found in its aglyconic form as oleuropein aglycone (OleA) (Figure 1). Oleuropein and its derivatives found in EVOO received particular attention due to their multiple important and protective functionalities, including antioxidant, antiviral, antitumor, antimicrobial, cardioprotective, hepatoprotective, neuroprotective, antiaging, antidiabetic, and anti-inflammatory effects. (23) Olive polyphenols, such as OleA and its main metabolite hydroxytyrosol, were studied for many years by us and other researchers regarding their effects on the aggregation pathways of various polypeptides involved in amyloid and neurodegenerative diseases, including Aβ peptide, tau protein, amylin, transthyretin, and α-synuclein. (24−31) While multiple effects of olive polyphenols have been detected at the molecular, cellular, and animal model levels, the specific mechanisms remain elusive, and important questions still need to be addressed as to whether there is a generic target or numerous targets along multiple aggregation pathways, which could be individual for each particular polypeptide. In particular, the reduced toxicity of the amyloids developed in the olive polyphenol presence was demonstrated in both cellular and murine models. In cultured cells, their amyloid protection was very significant and started at the level of the cellular membrane, perturbing various signaling pathways. (32,33) The experiments were carried out also on the TgCRND8 transgenic mouse model of plaque deposition; the mice were fed daily with an OleA or HT-integrated diet, and it was revealed that the animals displayed a strong improvement of the memory and behavioral deficits compared to untreated littermates. (34) These were accompanied by a substantial decrease in the quantities of amyloid plaques and the level of neuroinflammation. Moreover, a strong activation of the autophagic response was detected (34) with possible involvement of epigenetic modifications. (35)

Figure 1

Figure 1. Schematic presentation of the chemical structure of oleuropein and oleuropein aglycon (OleA).

High Resolution Image
Download MS PowerPoint Slide
Here, we studied the effect produced by OleA on S100A9 amyloid aggregation using a range of complementary methods in biophysics, biochemistry, cell biology, and advanced microscopy. We demonstrated how OleA mitigates S100A9 amyloid cytotoxicity in the human neuroblastoma SH-SY5Y cell line. Altogether, these findings shed light on the molecular and cellular determinants of OleA protection from toxic amyloids, highlighting the potential of olive polyphenols in averting AD and other neurodegenerative diseases associated with the amyloid-neuroinflammatory cascade.

Results and Discussion

Click to copy section linkSection link copied!

Inhibiting S100A9 Amyloid Aggregation by OleA

The kinetics of S100A9 amyloid formation in the presence of increasing OleA concentrations were carried out using the thioflavin-T (ThT) fluorescence assay as described previously (36) and shown in Figure 2A. S100A9 alone assembles into amyloid structures by the nucleation-dependent polymerization mechanism, (19,37) and its kinetics are characterized by the lack of a significant lag phase and steep growth phase, prior to reaching the plateau level. Upon an increase in the OleA concentrations, the slopes of amyloid growth, reflecting the kinetics rates, as well as the plateau levels where the amyloid assembly reached semiequilibrium noticeably decreased.OleA incubated alone under the same conditions did not interact with ThT as shown in Figure S1 and therefore did not contribute to the overall ThT signal in the corresponding mixtures. The initial parts of the S100A9 amyloid kinetic traces, corresponding to <20% maximal ThT fluorescence intensity values, were fitted using the nucleation-dependent polymerization model (38) (Figure 2B). The effective amyloid growth rate constants as well as the plateau levels were significantly decreased upon the increase in OleA concentrations (Figure 2C,D), reflecting the decrease in the overall amount of self-assembled amyloids.

Figure 2

Figure 2. Inhibition of S100A9 amyloid formation in the presence of increasing OleA concentrations observed by the ThT fluorescence assay and AFM. (A) S100A9 amyloid kinetics in the presence of increasing OleA concentrations monitored by the ThT assay. (B) Fitting of the initial parts of S100A9 amyloid kinetics with the nucleation-dependent polymerization model. (C) Ratios of the effective rate constants of S100A9 amyloid kinetics in the presence and absence of OleA (B0 is the effective rate constant in the absence of OleA, and B(c) is the rate constant at an OleA concentration of c). (D) Ratios of plateau intensities of S100A9 amyloid kinetics in the presence and absence of OleA (I0 is the plateau intensity in the absence of OleA, and I(c) is the plateau intensity at an OleA concentration of c). AFM images of S100A9 amyloid species without OleA and with increasing OleA concentrations after a 6 h (E–H) and 48 h (I–L) incubation, respectively. Amyloid fibril length distributions without OleA and with increasing OleA concentrations after a 6 h (M–P) and 48 h (Q–S) incubation, respectively, measured in AFM images. (T) Median length of S100A9 amyloid fibrils after a 6 h (black circles) and 48 h (red triangles) incubation, respectively, with increasing OleA concentrations. Molar ratios of S100A9 to OleA and the time of incubation are indicated in the figures. 100 μM S100A9, PBS, pH 7.4, and 42 °C. z-scale in the AFM images is indicated on the right with the bar color gradient from dark brown to light yellow. x,y-AFM scan sizes are 2 × 2 μm.

High Resolution Image
Download MS PowerPoint Slide
To monitor amyloid morphology during the amyloid self-assembly process, the atomic force microscopy (AFM) imaging was performed after a 6 and 48 h incubation of S100A9 samples in the presence and absence of OleA concentrations as demonstrated in Figure 2E–L. Already after a 6 h incubation, S100A9 alone formed flexible fibrils with ca. 2 nm height in the AFM cross sections and 0.28 ± 0.15 μm median length (Figure 2E,M). After a 48 h incubation, S100A9 fibrils grew in length, showing a broad distribution with 0.7 ± 0.4 μm median length, and collapsed and clumped aggregates were formed (Figure 2I,Q). Indeed, it has been demonstrated previously that S100A9 flexible fibrils tend to clump upon prolonged incubation. (39) Upon incubation with increasing OleA concentrations, the length and relative quantity of S100A9 amyloid fibrils captured by AFM imaging decreased after both 6 and 48 h incubation periods as demonstrated in Figure 2T. Importantly, the fibrils do not grow further upon increasing the incubation time from 6 to 48 h as summarized by presenting the median values of fibrillar length at different OleA concentrations in Figure 2T. The distributions of fibrillar length in the presence of OleA becomes significantly narrower compared to S100A9 alone (Figure 2M–S). The AFM heights of S100A9 fibrils in all samples remain about the same, ca. 2 nm, in the AFM cross sections. Interestingly, the decrease in fibrillar length in the presence of OleA correlates with the reduction of total amount of amyloids detected by ThT binding (Figure 2D,T).
The dot blot analysis indicates that the interaction of S100A9 aggregated samples with generic antiamyloid oligomer specific A11 antibodies is noticeable after a 6 h incubation and subsides upon an increase in the OleA concentration, being completely abolished at a S100A9 to OleA molar ratio of 1:10 (Figure S2). After a 48 h incubation, the amount of oligomeric species was significantly diminished in the S100A9 amyloid sample in the absence of OleA and completely absent in the presence of all concentrations of OleA.
Interestingly, upon the addition of OleA to preformed S100A9 fibrils assembled during the 48 h incubation, we observed the decrease of ThT fluorescence, indicating the decrease of amyloid quantity in these samples (Figure 3A). AFM imaging demonstrated that flexible fibrils of S100A9 observed prior to the addition of OleA (Figure 3B) have collapsed into nonfibrillar aggregates after the addition of OleA, i.e., at a 1:2 molar ratio of S100A9 to OleA (Figure 3C).

Figure 3

Figure 3. Preformed S100A9 fibrils disintegrated by OleA. (A) Decrease of ThT dye fluorescence upon the addition of OleA to S100A9 fibrils formed after a 48 h incubation. (B) AFM images of S100A9 fibrils without OleA. (C) AFM image of S100A9 aggregates after the addition of 137 μM OleA to the sample shown in (B). 75 μM S100A9 was subjected to fibrillation in PBS, pH 7.4, at 42 °C. Scan sizes are 2.5 × 2.5 μm.

High Resolution Image
Download MS PowerPoint Slide
The far-UV circular dichroism (CD) spectrum of native S100A9 is characteristic for α-helical protein, displaying minima at 222 and 208 nm, and it was not perturbed upon the addition of OleA (Figure 4). This indicates that OleA perturbs the S100A9 structure locally rather than globally. The spectrum of fibrillated S100A9 displayed some changes in its shape with a broad minimum of ellipticity at 214–216 nm, reflecting the development of the β-sheet. It is not excluded that some α-helical structure was preserved in the S100A9 fibrils, since the spectrum is broader then the typical β-sheet spectrum; i.e., the remaining α-helices still can be packed at the fibrillar interface. When S100A9 was incubated in the presence of OleA to induce its amyloid formation, the shape of the CD spectrum remained close to the native-like one, demonstrating that OleA indeed inhibits amyloid development. Interestingly, when OleA was added to the preformed fibrils of S100A9, it induced the changes in the far-UV CD spectrum, which resembles a mixture of α-helices and β-sheets. This indicates that some reduction of the β-sheet content took place (Figure 4), which corresponds to the nonfibrillar aggregate formation described above (Figure 3).

Figure 4

Figure 4. Far-UV CD spectra of native and amyloid S100A9 and the OleA effect on them. Spectra were recorded at 25 °C at the following conditions: 75 μM S100A9 in all samples and 1:2 S100A9 to OleA molar ratio, if OleA is added. PBS, pH 7.4. S100A9 fibrils were formed during the 48 h incubation at 42 °C. Labeling of the samples is shown in the legend.

High Resolution Image
Download MS PowerPoint Slide
Thus, all above experiments demonstrate consistently that OleA produces a significant inhibiting effect on S100A9 amyloid formation by inhibiting its amyloid oligomerization (dot blot analysis with A11 antibodies) and cross-β-sheet formation (far-UV CD), reducing the effective rate of amyloid assembly (kinetic assay), reducing the length of amyloid fibrils (AFM), and thus diminishing the overall quantity of the amyloids (ThT fluorescence and AFM). Moreover, OleA is able to convert the already preformed S100A9 fibrils into unstructured aggregates and potentially make them more susceptible to the clearance process in the body.

Interaction of OleA with Native and Amyloid S100A9 followed by Intrinsic Fluorescence

To shed light on OleA interactions with native and amyloid S100A9, we have titrated both samples with increasing concentrations of OleA and followed the changes by the intrinsic fluorescence of Trp 88. For the titration, we used the S100A9 amyloid sample incubated for 24 h at a 100 μM concentration and subsequently diluted it to 4 μM to prevent fibrillar clumping (Figure 2), and native S100A9 was also taken at 4 μM (both in monomer equivalent). In both samples, we have observed a decrease of the intrinsic fluorescence intensities upon an increase in the OleA concentrations, demonstrating nonhyperbolic concentration dependences, which were fitted with a two binding site model as shown in Figure 5A–C. Both fitting curves were largely overlapped, suggesting the same binding sites in the native and amyloid S100A9 species. Since OleA itself can associate into dimer, trimer, and larger species (40) and act as a fluorescence quencher of Trp fluorescence, (29) the apparent dissociation constants (Kd) of 0.5 and 200 μM may reflect the cumulative effect of binding and fluorescence quenching produced by the OleA polymorphic species.

Figure 5

Figure 5. Interaction of native and amyloid S100A9 with OleA monitored by intrinsic fluorescence. Fluorescence spectra of native (A) and amyloid (B) S100A9 upon increasing concentrations of OleA. (C) Relative fluorescence intensities at the spectral maximum of native (blue triangles) and amyloid (red circles) S100A9 upon increasing OleA concentrations. Fitting curves are shown by solid lines in the corresponding color. The two binding site model is shown in the inset. (D) Shifts of fluorescence spectral maxima of native and amyloid S100A9 determined by the first derivative method upon increasing OleA concentrations shown in the same symbols as in (C). Four μM S100A9, PBS, pH 7.4, and 42 °C.

High Resolution Image
Download MS PowerPoint Slide
Interestingly, native and amyloid S100A9 are characterized by different fluorescence maxima of 343 and 337 nm, respectively, indicating that within the fibrils Trp 88 is present in the more hydrophobic environment. The fluorescence spectral maxima of both native and amyloid S100A9 samples were shifted by ca. 3 nm toward the shorter wavelengths upon an increase in the OleA concentrations (Figure 5D), indicating that in both species Trp 88 becomes even more buried into the hydrophobic interior upon OleA binding.

MD Simulation of the OleA Interaction with S100A9

To shed further light on OleA interactions with S100A9, we have performed the MD simulation of the native S100A9 dimer in the presence of two molecules of monomeric OleA, taking into account that S100A9 self-assembles into a homodimer under native and also destabilizing conditions (11,37) (Figure 6). The S100A9 dimer is characterized by a flat surface with no deep cavities, and molecular docking reveals only one major OleA binding site per subunit (Figure 6A). The B-factor presentation of the S100A9 molecules shows that OleA docks into the least mobile part of the S100A9 structure (Figure 6B). (41) The space filling presentation of the S100A9 dimer with the hydrophobic and charged/hydrophilic residues indicates that OleA binds in a shallow hydrophobic cavity in each subunit (Figure 6C) by forming several dynamic H bonds (Figure 6D). Specifically, these are the hydrogen bonds between S100A9 Glu 72 and the OH group on the OleA aromatic ring, Glu 52, and methyl-ester end of OleA as well as Arg 85 and the carbonyl oxygen on OleA (Figure 6D). In addition, π–π stacking interactions between the Trp 88 and OleA aromatic ring are formed (Figure 6D). The number of dynamic hydrogen bonds per time frame between each OleA molecule and S100A9 subunit varies between 1 and 3 (Figure 6E), which together with π–π stacking interactions may ensure micromolar to submicromolar binding affinities, observed in the fluorescence titration measurements (Figure 5). The root mean square deviation (RMSD) graph demonstrates that, due to the lack of a well-defined binding cavity, OleA molecules may dissociate from the S100A9 dimer after ca. 15 ns (Figure 6F). The high mobility of OleA at the S100A9 surface can disrupt the optimal protein–ligand orientations and the maximal number of binding interactions, suggesting that OleA binding may involve multiple events. The high-affinity interactions reflect the optimal ligand–protein orientation and the maximal number of binding interactions, while the suboptimal orientation and lower number of binding interactions may contribute to the lower binding affinities, consistent with the fluorescence titration experiments (Figure 5). OleA binding to the S100A9 dimer does not perturb its α-helical secondary structure beyond the binding site, which is consistent with the CD measurements described above.

Figure 6

Figure 6. MD simulation of the interactions of native S100A9 with OleA. (A) Binding of one OleA molecule per subunit of S100A9 dimer. S100A9 monomers are shown by the ribbon diagram in yellow and green colors, respectively. The amino acid side chains of S100A9, which form binding interactions with OleA, are shown by cyan sticks. OleA molecules are shown by magenta sticks. OleA forms hydrogen bonds with Glu 52 and Arg 85 and π–π stacking interactions with Trp 88. (B) B-factor presentation of the S100A9 dimer backbone shows that OleA (in black sticks) binds to the protein site with low mobility (shown in blue). The loops with high mobility are shown by thicker tubes with a color gradient from yellow to red, corresponding to increasing mobility. (C) S100A9 dimer surface presentation in space filling and colors based on the polarity of the amino acid residues: hydrophilic residues, blue; hydrophobic residues, brown; residues with intermediate properties, white. OleA (shown by sticks) binds to a shallow hydrophobic cavity on the S100A9 surface. (D) Detailed presentation of the OleA orientation and binding interactions (presented in yellow) highlighting: π–π stacking between Trp 88 and OleA, hydrogen bonding between Arg 85 and the carbonyl oxygen of OleA, and the proximity between Glu 52 and the ester group of OleA. (E) Number of hydrogen bonds between each OleA molecule and S100A9 dimer. OleA molecules dissociate when the number of hydrogen bonds falls to zero. Hydrogen bonds were defined as the interactions between the polar groups with an angle of less than 20° and less than 3.0 Å distance. (F) Root mean square deviation (RMSD) values demonstrating the mobility of each OleA molecule and S100A9 dimer. Ligand dissociation results in the rapid increase in the RMSD values.

High Resolution Image
Download MS PowerPoint Slide
Thus, the combined fluorescence titration and MD simulation experiments demonstrate consistently that OleA indeed interacts with native S100A9. The interactions involve multiple binding events due to the lack of specific OleA binding cavities on the S100A9 molecule (Figure 4C) similar to its interactions with other previously studied amyloidogenic polypeptides. (24,26,29,32) Moreover, OleA can self-assemble into a larger species, (40) which may also affect its apparent binding affinity. These were further supported by the similar binding of OleA with both native and amyloid S100A9 (Figure 5C).

OleA Alleviates S100A9 Induced Cytotoxicity Measured by the MTT Assay

The effect of OleA on the S100A9 cytotoxicity induced in the neuroblastoma SH-SY5Y cell line was studied by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assay. Initially, neuroblastoma cells were treated for 24 h with various concentrations of S100A9 alone in either native or 48 h aged amyloid form (Figure S3A). S100A9 amyloids were more cytotoxic, reducing the cell viability by ca. 40–50% at 20 to 40 μM concentrations; native S100A9 also reduced the cell viability by ca. 20–30% at similar concentrations (Figure S3A). Since S100A9 is an alarmin and pro-inflammatory protein, it can induce cellular toxicity also in its native state via activation of RAGE and TLR-4 receptors. (42,43)
Then, SH-SY5Y cells were exposed for 24 h to 20 μM of either native or amyloid S100A9 samples aged for 24 and 48 h, respectively, under aggregating conditions (Figure 7A). All samples were prepared both without or with OleA at the following S100A9 to OleA molar ratios: 1:1, 1:2, 1:5, and 1:10 (in monomeric equivalent). Using the MTT test, we found that the S100A9 amyloids aged 24 and 48 h without OleA displayed the same cytotoxic effect, decreasing cell viability by about 40% (Figure 5A). Their cytotoxicity was mitigated, however, if S100A9 aggregates were incubated in the presence of OleA, then the cell viability was fully recovered at both 1:5 and 1:10 of S100A9 to OleA molar ratios (Figure 7A). Similar trend was observed for native S100A9, where the recovery of cytotoxicity correlated with the increasing concentrations of OleA, and full recovery was achieved at a 1:5 of S100A9 to OleA molar ratio.

Figure 7

Figure 7. Cytotoxic effect of the S100A9 amyloids in the SH-SY5Y cells is mitigated by OleA. (A) Viability of SH-SY5Y cells measured by the MTT assay and (B) ROS levels in the SH-SY5Y cells measured by DCFDA fluorescence. Cells were exposed to 20 μM S100A9 samples for 24 h. S100A9 was added in either native or amyloid forms, which were incubated for 24 and 48 h in PBS, pH 7.4, at 42 °C, respectively, prior the addition to the cells. S100A9 to OleA molar ratios were 1:0, 1:1, 1:2, 1:5, and 1:10 as indicated along x-axis. The control corresponds to the untreated cells and is shown by a single black bar, where the absence of S100A9 and OleA is indicated as (0:0). The experimental bars corresponding to the addition of native S100A9 are shown in black, the addition of 24 h aged S100A9 amyloids are shown in gray, and the 48 h aged amyloids are shown in white. Error bars indicate the standard error of the mean of the independent experiments carried out in triplicate. ***p < 0.001 and **p < 0.01 versus control (0:0). °p < 0.05 and °°p < 0.01 versus cell viability in the presence of native or the corresponding aggregated S100A9 without OleA, i.e., molar ratio (1:0). (C) Confocal microscopy imaging of the intracellular free Ca2+ levels in the SH-SY5Y cells exposed for 10, 30, and 60 min to 20 μM S100A9 amyloids incubated for 48 h in the absence or in the presence of OleA at the molar ratios of S100A9 to OleA indicated in the figure. Scale bars are 14 μm in all images.

High Resolution Image
Download MS PowerPoint Slide
The cytotoxicity of the preformed fibrils of S100A9 treated with OleA was also tested on the SH-SY5Y cells by the MTT assay. The results are shown in Figure S4. We observed a decrease of the cytotoxic effect of the preformed S100A9 amyloids when they were treated with OleA at a 1:2 molar ratio of S100A9 to OleA from 1 to 48 h. This data suggests that after 48 h of coincubation OleA disassembles already formed S100A9 fibrils into nonfibrillar aggregates as shown in Figure 2C, that are no longer toxic. Such an inhibitory effect was also observed after shorter treatment times, suggesting that OleA likely makes the fibrils harmless by solvating them before inducing their collapse into unstructured aggregates.

OleA Mitigates the Perturbations in Reactive Oxidative Species (ROS) and Intracellular Ca2+ Levels Induced by S100A9 Amyloids

Free Ca2+ levels and reactive oxidative species imbalances are involved in the cellular toxicity of amyloid. (44,45) Here, we examined whether OleA can act as a protective agent in these processes as well. Intracellular ROS levels were measured using the fluorescent probe CM-H2DCFDA (Figure 7B). In the cells exposed to native S100A9 as well as to the 24 and 48 h aged S100A9 amyloids, the ROS levels were increased by ca. 1.5-, 2.0-, and 2.8-fold, respectively, compared to untreated cells. Remarkably, the presence of OleA reduced ROS production in all cells exposed to both native and amyloid S100A9. The ROS level returned to the level of untreated cells at 1:5 and 1:10 ratios of S100A9 to OleA (Figure 7B).
We evaluated the changes of intracellular free Ca2+ levels in neuroblastoma cells treated with native S100A9 and S100A9 amyloids aged for 24 and 48 h using confocal microscopy with the Fluo-3-acetoxymethyl ester (Fluo-3AM) Ca2+ indicator (Figure S3B). Native S100A9 did not cause an increase in the free Ca2+ level after the addition to SH-SY5Y cells from 10 to 60 min, while both aged amyloid samples led to a similar increase of intracellular Ca2+, which was manifested in Fluo-3AM fluorescence (Figure S3B). Therefore, in further experiments, only the 48 h aged S100A9 samples were used with increasing OleA concentrations (Figure 7C). When the cells were treated with a 1:1 molar ratio of S100A9 to OleA, Fluo-3AM fluorescence subsided significantly. Remarkably, it returned to the level of untreated cells when SH-SY5Y cells were exposed to the samples with 1:5 and 1:10 of S100A9 to OleA molar ratios. This is consistent with the protective effect of OleA observed by MTT cell viability and the ROS assays presented above (Figure 7A,B).

Effect of S100A9 Amyloids on Differentiated SH-SY5Y Neuroblastoma Cells

To compare the susceptibility of undifferentiated and differentiated SH-SY5Y cells to S100A9 amyloids, we repeated the MTT and ROS assays on differentiated SH-SY5Y cells. The cells were exposed for 24 h to 20 μM S100A9 fibrils (equivalent of the monomer concentration). The differentiated cells appeared to be slightly more susceptible to the amyloid induced damage in terms of both cell viability and ROS production (Figure S5). In agreement with our unpublished data, the different cell susceptibility could be due to a different poly- and monosialic acid expression on the plasma membrane. However, in this paper, we focused on the undifferentiated SH-SY5Y cells to compare our results with previously published studies. (11)

OleA Interferes with S100A9 Amyloid Binding to Cell Membrane Rafts Studied by Immunofluorescence and Fluorescence Resonance Energy Transfer (FRET)

The direct binding of amyloids to plasma membranes is a critical step in amyloid cytotoxicity. (46,47) Notably, amyloids can accumulate in membrane rafts, containing monosialotetrahexosylganglioside-1 (GM1). (48) The amyloid binding leads to structural and functional perturbations of the cell membrane, affecting signaling pathways (49−51) and altering intracellular free Ca2+ and ROS levels. (44,52) In addition, many papers have reported the effect on signaling pathways by direct binding of amyloids to cell membrane receptors. (52−55) Therefore, we performed immunofluorescence assay with the GM1 and S100A9 specific fluorescently labeled antibodies using confocal microscopy and sensitized FRET analysis to evaluate the interactions between the membrane ganglioside GM1 and S100A9 amyloids produced after the 48 h incubation in the absence or presence of OleA. Confocal imaging revealed that the amyloid assemblies were accumulated at the SH-SY5Y plasma membrane and colocalized with GM1 rafts (Figure 8A,E). Moreover, a strong FRET signal indicates close spatial localization and even direct interactions of the S100A9 amyloids with the membrane GM1 (Figure 8I). When the cells were subjected to S100A9 amyloids developed at increasing OleA concentrations, we observed both smaller clusters of aggregates on the cell membrane (Figure 6F–H) and a reduced FRET signal (Figure 8J–L). Furthermore, to assess the direct involvement of ganglioside GM1 in the binding of S100A9 amyloids to the cell membrane, we also conducted immunofluorescence experiments after treating the cells with the ganglioside synthesis inhibitor d-threo-1-phenil-2-decanoylamino-3-morpholino-1-propanol (d-PDMD). We found that the binding of S100A9 fibrils to membrane rafts was significantly reduced in cells depleted of GM1, following their treatment with d-PDMD (Figure 8M,N). These data support the conclusion that the binding sites of S100A9 amyloids to the cell membrane occur at the raft domains. These observations also suggest the critical role of GM1 in binding of S100A9 amyloids to the cell membrane, most likely due to the clusters of sialic acid moieties, producing negatively charged regions at the cell surface. All results signify the roles of the amyloid–membrane interactions in triggering cellular toxicity and the importance of OleA in reducing cytotoxicity and perturbations of intracellular Ca2+ and ROS levels induced by S100A9 amyloids.

Figure 8

Figure 8. Immunolocalization of S100A9 aggregates on the SH-SY5Y plasma membrane. Confocal microscopy imaging of SH-SY5Y cells exposed for 24 h to 20 μM S100A9 aggregated for 48 h in the absence or in the presence of different molar ratios of S100A9 to OleA as indicated in the figures. The cell membranes were stained with Alexa 488-conjugated CTX-B (green fluorescence); cell nuclei were stained with Hoechst 33342 (blue fluorescence), and protein aggregates were stained with anti-S100A9 antibodies followed by treatment with Alexa 568-conjugated antirabbit secondary antibodies (red fluorescence). The mergence of the channels is shown in (A–D). Zoomed areas from (A–D) are shown in (E–H). FRET efficiency in those areas is shown in (I–L). (M) S100A9 do not bind to membrane rafts in the SH-SY5Y cells pretreated with an inhibitor of the GM1 synthesis as revealed by the lack of FRET efficiency. The control corresponds to the untreated cells. The SH-SY5Y cells were pretreated with 10 μM PDMD for 48 h (indicated as CTRL-PDMP) to reduce GM1 on the cell surface and then incubated for 24 h with 20 μM S100A9 fibrils (in monomer concentration). (N) Quantification of green fluorescence per cell, indicating the reduction of GM1 in cell membranes. Error bars indicate the standard error of three independent experiments. *p < 0.001 versus control.

High Resolution Image
Download MS PowerPoint Slide

Concluding Remarks

Click to copy section linkSection link copied!
Here, for the first time, we have demonstrated that the most abundant polyphenol in olive oil, OleA, has multiple potencies in the inhibition of the amyloid self-assembly of pro-inflammatory protein S100A9 and mitigation of its damaging effect on neuroblastoma SH-SY5H cells. By directly interacting with native and fibrillar S100A9, OleA acts via multiple mechanisms and pathways to inhibit S100A9 amyloid aggregation; i.e., it prevents amyloid oligomerization and cross-β-sheet formation, reduces the effective rate of amyloid growth and the length of amyloid fibrils, and diminishes the overall amyloid load. Moreover, OleA is able to disintegrate already preformed fibrils of S100A9, converting them into nontoxic aggregates, which do not bind ThT dye, characteristic for cross-β-sheet amyloids. Furthermore, OleA targets S100A9 amyloids at the cellular membrane, protecting cells from amyloid cytotoxicity and amyloid-induced increased levels of ROS and free Ca2+. Since S100A9 is both a pro-inflammatory and amyloidogenic protein, OleA effectively mitigates the pathological consequences of the S100A9-driven amyloid-neuroinflammatory cascade in neurodegenerative diseases. (9−11) Together with previously reported antiamyloid effects of OleA on other amyloidogenic polypeptides, (25−33) the present findings further emphasize the beneficial properties of the Mediterranean diet in which olive oil is a central component.

Methods

Click to copy section linkSection link copied!

Amyloid Fibril Formation

S100A9 protein was expressed in E. coli and subjected to purification procedures as reported previously. (56) Lyophilized S100A9 was dissolved in PBS buffer at pH 7.4, with all solutions remaining on ice. In order to remove any aggregates, all S100A9 solutions were filtered through a 0.22 μm spin membrane filter prior to subjecting them to the amyloid incubation. To form amyloids, S100A9 was incubated in PBS, pH 7.4, at 42 °C. Previously, we have conducted extensive kinetics experiments on S100A9 amyloid formation at both 37 and 42 °C (19) as well as at 55 °C. (57) The scaling of the corresponding kinetics rate constants versus temperature illustrated that the mechanism of S100A9 amyloid self-assembly remained the same in this wide temperature range, which is below the thermal unfolding transition of S100A9, occurring above 60 °C. (56) The morphology of amyloid fibrils, developed in this temperature range and followed by AFM, remained also the same. (19,57) We selected the arbitrary condition at 42 °C in this research to speed up the amyloid self-assembly without altering the basic mechanism.

Preparation of OleA

Oleuropein (extrasynthese) was deglycosylated by subjecting it to almond β-glucosidase treatment (EC 3.2.1.21, Fluka, Sigma-Aldrich) as specified previously. (27) 10 mM oleuropein in 310 μL of 0.1 M sodium phosphate buffer, pH 7.0, was incubated with 8.9 IU of β-glucosidase overnight at room temperature (RT) and centrifuged at 18 000 rpm for 10 min. The pellet containing the deglycosylated OleA was resuspended in 100 mM stocks using DMSO, frozen, protected from light, and once opened, used within 24 h. The deglycosylation was verified by assaying in the supernatant the levels of glucose using the Glucose assay kit (HK, Sigma-Aldrich).

Dissolving OleA

OleA was dissolved in 20% DMSO to reach a 50 mM concentration. A second dilution was made in 200 μL of PBS to reach a 5 mM concentration of OleA. Samples were sonicated during 2 min to dissolve the entire sample and manipulated at RT in the dark during the experiments. In the concentration-dependent experiments, OleA was subsequently diluted to 100, 200, 500, and 1000 μM. The same percentage of DMSO (0.4%) was kept in all solutions.

ThT Fluorescence Assay

ThT is a fluorescence dye that binds to the β-sheet containing amyloid structures; this leads to an increase of its fluorescence and thus enables the kinetics of amyloid formation to be followed and quantified. The ThT assay was performed as described previously. (36) 100 μM S100A9 was transferred into Corning 96 black well plates with transparent bottoms, and then, 20 μM ThT was added to every well. Sample volumes were kept at 200 μL per well. The 96 well plates were covered, transferred immediately into a Tecan F200 PRO plate reader, and subjected to incubation at 42 °C during 50 h by applying 432 rpm orbital shaking every 10 min. Fluorescence of ThT dye was recorded every 10 min. A filter at 430 nm was used for excitation, and a filter at 495 nm was used for emission; both filters were characterized by 20 nm band widths. All protein solutions were incubated in triplicates.

AFM Imaging

AFM imaging was performed in air using a BioScope Catalyst AFM (Bruker) operating in a peak force mode. The scan rate was set at 0.51 Hz, and a scan resolution of 512 × 512 pixels was used. Bruker MSLN and SLN cantilevers were used in all measurements. Imaging was also conducted using a PicoPlus AFM (Molecular Imaging) equipped with a 100 μm scanner operating in tapping mode in air. The resonance frequency was set in the 170 to 190 kHz range; the scan rate was at 1 Hz, and the scan resolution was at 512 × 512 pixels. For ambient AFM imaging, 20 μL samples were deposited on freshly cleaved mica, kept for 30 min, washed 5 times with 200 μL deionized water, and left to dry at RT. The heights of the amyloid structures were measured in their AFM cross sections using Bruker Nanoscope AFM analysis software, and the amyloid fibril lengths were measured using ImageJ software.

Dot Blot Analysis

S100A9 amyloid samples incubated with and without OleA were examined in dot blot experiments using amyloid oligomer specific antibodies. (58) 2 μL of the amyloid sample was deposited on a nitrocellulose membrane (Fisher Thermo Scientific) and dried at RT for 15 min. Nonspecific antigen sites were blocked using 3% bovine serum albumin (BSA) in Tris buffer saline containing 0.05% Tween-20 (TBS-T) for 1.5 h at RT. Then, the nitrocellulose membrane was subjected to incubation with primary antibodies, i.e., rabbit A11 generic amyloid oligomer specific antibodies produced by Kayed et al., (58) and dissolved in 0.5% BSA in TBS-T for 30 min at RT. After that, the nitrocellulose membrane was washed 3 times with TBS-T for 5 min each wash and incubated with the secondary antibodies, i.e., antirabbit IgGs conjugated with horseradish peroxidase (AS10668 lot 1809 Agrisea), for 45 min at a 1:500 dilution at RT. The nitrocellulose membrane was washed 2 times with TBS-T and 1 time with TBS for 15 min each wash. After the addition of enhanced chemiluminescence reagent for 1 min, the membrane was subjected to the measurement of chemiluminescence by a Bio-Rad ChemiDoc Imaging System. The density of blots was measured using an ImageJ software.

Titration of Native and Aggregated S100A9 by OleA Using Intrinsic Fluorescence

4 μM samples of either native or 24 h aged amyloid S100A9 were titrated by OleA in a 2 mm path length quartz cuvette using degassed PBS, pH 7.4, at RT. Intrinsic fluorescence spectra were acquired using a FP 6500 Jasco spectrofluorometer at RT. Excitation wavelength was set at 280 nm; fluorescence emission was recorded between 295 and 450 nm, and both excitation and emission slits were set at 3 nm. The spectra were obtained by averaging 3 scans recorded at a 200 nm/min rate. The OleA spectra at each added concentration were subtracted from those of S100A9.

Titration of S100A9 Amyloids by OleA Monitored by ThT Fluorescence

150 μM S100A9 was aggregated for 48 h in degassed PBS, pH 7.4, at 42 °C. 20 μM ThT was added to each amyloid sample; then, they were diluted to a 75 μM S100A9 concentration. The titration by OleA was performed using 2 mm quartz cuvettes in a FP 6500 Jasco spectrofluorometer at RT. Excitation wavelength was set at 450 nm; fluorescence emission spectra were recorded between 480 and 550 nm, and both slits at excitation and emission were set at 10 nm. The spectra were obtained by averaging 3 scans recorded at a 200 nm/min rate.

Fitting the Kinetics of S100A9 Amyloid Formation in the Absence and Presence of OleA

The S100A9 amyloid kinetics in the absence and presence of OleA were fitted using a nucleation dependent polymerization model. (38) The initial parts (<20% plateau level) of the kinetic curves were fitted using the following equation:
where I0 is the fluorescence intensity at the <20% plateau level and B0 is the effective rate constant, combining microscopic nucleation and growth constants.

Fitting the Titration of S100A9 by OleA Monitored by Intrinsic Fluorescence

The maximum positions of the fluorescence spectra of S100A9, containing a single Trp 88 residue, were determined using a first derivative method. Prior to this, all spectra were smoothed by the Eilers smoothing algorithm, minimizing the noise level. (59) The smoothing parameter λ was 105, and the smoothing order was 3. The fluorescence intensity at the spectral maximum and the spectral maximum position errors were calculated by taking into account the instrument accuracy (Jasco FP6500), and 3 spectral replicates were recorded at each OleA concentration. The titration curve of S100A9 by OleA followed by fluorescence intensity at the spectral maximum was fitted by the two binding site model, (60) relating four parameters:
where F is the fluorescence intensity of S100A9 in the presence of each OleA concentration, F0 is the fluorescence intensity of S100A9 in the absence of OleA, f1 is the fractional occupancy of binding sites with affinity K1, and f2 is the fractional occupancy of binding sites with affinity K2.

Far-UV CD

CD spectra were recorded using a Jasco J-810 spectropolarimeter. The measurements were performed in a quartz cuvette with 1 mm spectral pathway, and 3 repeats were averaged.

MD

All atom MD calculations used the GROMACS 2019.3 program and protocols that were descried in our earlier studies. (37)

Molecular Docking Studies

Possible binding sites for OleA on the S100A9 surface were at first explored by searching for hydrophobic patches and cavities on the protein Connolly surface. (61) Docking positions were calculated using RxDock and AutoDock Vina 1.1.2. (62,63) The ligands were hydrogenated and charged at pH 7.0 using the Gasteiger protocol. Proteins were protonated at pH 7.0 using the AMBER98S force field. The molecular structures for OleA were taken from ChemSpider and PubChem databases. The S100A9 structure was downloaded from the protein data bank, PDB: 5I8N.

All-Atom Molecular Dynamics Studies

For MD computation, the S100A9-OleA complex was prepared using CHARMM-GUI solution builder. (64) In our simulations, we used 85 080 water molecules (TIP3), 272 potassium ions (POT), and 221 chlorine ions (CLA). The simulation box was 112 × 112 × 112 Å3 in size and contained 254 871 atoms. The system was relaxed using a sequence of equilibration steps at 303.15 K using Nose-Hoover coupling, and the pressure was set to 1.0 bar using semi-isotropic Parinello-Rahman coupling. The constraint algorithm was LINCS, and the cutoff scheme was Verlet. Two minimization steps and one equilibration step were used for the system relaxation. The simulations analyzed molecular processes for 100 ns on a molecular time scale in 50 million steps with the step size set to 2 fs. The ligand parametrization was prepared using ACPYPE tools (65) or the CHARMM-GUI Ligand Reader & Modeler for the calculation of CHARMM-compatible topology and parameter files. (66) All simulations used GROMACS version 2019.4. (67)

Neuroblastoma Cell Culture

Human neuroblastoma SH-SY5Y cells were grown in a 5.0% CO2 humidified atmosphere at 37 °C in 50% HAM, 50% DMEM, containing 10% fetal bovine serum (FBS), 3.0 mM glutamine, 100 units/mL penicillin, and 100 μg/mL streptomycin. The materials used for cell culture were from Sigma-Aldrich. To assess cell viability by the MTT reduction assay, neuroblastoma cells were grown in a 96 well plate at 15 × 103 cells/well, while for immunofluorescence staining, they were cultured in a 24 well plate at 3 × 104 cells/well. The nuclei of the cells were stained with 0.5 μg/mL Hoechst 33342 (Sigma-Aldrich) during a 30 min incubation at 37 °C; then, the cells were rinsed twice with PBS, and complete medium was added.

Differentiating Neuroblastoma Cells

SH-SY5Y cell differentiation was induced by growing the cells for 7 days in culture medium supplemented with 3% FBS and 10 μM retinoic acid, (68) and then, the cells were treated with S100A9 amyloids.

MTT Viability Assay

The MTT cell metabolomic activity assay optimized for the SH-SY5Y cell line was performed to assess the cell viability. First, the neuroblastoma cell line was seeded and grown for 24 h in 96 well plates in complete medium. Then, the cells were treated for 24 h with 20 μM S100A9 in the native or aggregated state in the absence or presence of increasing OleA concentrations. After 24 h of coincubation of the cells with protein samples, the culture medium from each well was discarded and the cells were incubated for a further 1 h at 37 °C with 100 μL of serum free without phenol red DMEM containing 0.5 mg/mL 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) dye. Subsequently, cells were lysed by adding 100 μL of solubilizing solution (20% SDS, 50% N,N-dimethylformamide). After 2 h of lysis at 37 °C, the absorbance value of blue formazan, produced by viable cells, was determined by a spectrophotometric microplate reader at 570 nm. The average values were calculated from triplicate readings and subtracted from the blank value.

Intracellular ROS Levels

Intracellular ROS levels were measured using fluorescent probe 2′,7′-dichlorofluorescein diacetate acetyl ester (CM-H2DCFDA, Thermo Fisher Scientific), which permeates the cell membrane and then becomes hydrolyzed and oxidized by radical species to fluorescent product, DCF. The formation of this product was monitored by the increase of fluorescence at 538 nm. SH-SY5Y cells were seeded in 96 well plates (3 × 104 cells/well) and, after 24 h, were exposed during a further 24 h to 20 μM S100A9 in the native or aggregated form with or without increasing OleA concentrations. After that, DMEM, without phenol red and supplemented with 10 μM CM-H2DCFDA, was added to each well, and the samples were incubated for 30 min in the dark at 37 °C. The fluorescence at 538 nm was measured using a Fluoroscan Ascent FL (Thermo Fisher Scientific).

Cytosolic Levels of Free Calcium Measured by Confocal Imaging

Fluorescent probe Fluo-3 acetoxymethyl ester (Fluo-3, Thermo Fisher Scientific) was used to detect intracellular levels of free Ca2+. Subconfluent neuroblastoma cells grown on glass coverslips were loaded with 5.0 μM Fluo-3 at 37 °C for 5 min and then treated for 10, 30, or 60 min with S100A9 aggregates formed after a 48 h incubation either without OleA or with OleA at different S100A9 to OleA molar ratios (1:1, 1:5, and 1:10). Finally, the cells were fixed for 10 min in 2.0% paraformaldehyde in PBS. Imaging was carried out using a confocal Leica TCS SP8 scanning microscope with a Leica Plan 7 Apo 40× oil immersion objective.

Immunofluorescence Confocal Imaging of S100A9 Amyloid Interactions with Cell Membranes

Subconfluent neuroblastoma cells were seeded on glass coverslips and exposed for 24 h to 2.0 μM S100A9 amyloids incubated for 48 h either without OleA or with OleA at different S100A9 to OleA molar ratios (1:1, 1:5, and 1:10). After cell washing with PBS, gangliosides GM1 in live cell plasma membranes were labeled with 10 ng/mL cholera toxin B-subunit (CTX-B) conjugated with Alexa 488 (Thermo Fisher Scientific) in fresh complete medium for 10 min at RT. Cells were subsequently fixed by 2.0% paraformaldehyde in PBS for 10 min and treated with a 1:1 acetone/ethanol solution for 4.0 min at RT to allow cell permeabilization. After thorough PBS washing, the blocking was performed using PBS containing 0.5% BSA and 0.2% gelatin for 1 h at 37 °C. S100A9 in the neuroblastoma cell membranes was stained for 1.0 h at RT with rabbit anticalgranulin B (B-5) monoclonal antibody (sc-376772, Santa-Cruz Biotechnology) diluted to 1:300 in the blocking solution. Then, the cells were washed 3 times with PBS for 30 min under stirring, and then, Alexa 568 conjugated antirabbit secondary antibodies (Thermo Fisher Scientific) diluted to 1:100 in PBS were added for 30 min at RT. Finally, the samples were washed twice in PBS and once in distilled water, and the coverslips were mounted. Fluorescence imaging was performed using a Leica TCS SP8 AOBS confocal scanning microscope. Cell imaging was acquired in at least two different experiments using a Leica HC PL Apo CS2 63× oil immersion objective. Spectral analysis of the FRET interaction between Alexa 488 fluorophore conjugated with CTX-B and Alexa 568 fluorophore on immunolabeled S100A9 was carried out by the FRET sensitized emission method, as previously reported. (32,69)

Statistical Analysis

One-way analysis of variance by ANOVA and pairwise comparisons by the Tukey HSD (honestly significant difference) method were used for the statistical evaluation of the data.

Supporting Information

Click to copy section linkSection link copied!

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acschemneuro.0c00828.

  • Time dependences of ThT fluorescence during OleA incubation; interaction of S100A9 amyloids with A11 amyloid oligomer specific antibodies upon increasing OleA concentration; cell viability and intracellular free Ca2+ level in SH-SY5Y cells affected by S100A9 amyloids; preformed S100A9 fibrils treated with OleA during various times; cytotoxicity of S100A9 fibrils to undifferentiated and differentiated SH-SY5Y cells (PDF)

Terms & Conditions

Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Author Information

Click to copy section linkSection link copied!
  • Corresponding Authors
  • Authors
    • Manuela Leri - Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50134 Florence, Italy;  Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, 50139 Florence, Italy
    • Himanshu Chaudhary - Department of Medical Biochemistry and Biophysics, Umeå University, 90187 Umeå, Sweden
    • Igor A. Iashchishyn - Department of Medical Biochemistry and Biophysics, Umeå University, 90187 Umeå, Sweden;  Orcidhttps://orcid.org/0000-0002-1691-9025
    • Jonathan Pansieri - Department of Medical Biochemistry and Biophysics, Umeå University, 90187 Umeå, Sweden;  Orcidhttps://orcid.org/0000-0001-8918-9943
    • Željko M. Svedružić - Department of Biotechnology, University of Rijeka, HR 51000 Rijeka, Croatia;  Orcidhttps://orcid.org/0000-0002-0736-6182
    • Silvia Gómez Alcalde - Department of Medical Biochemistry and Biophysics, Umeå University, 90187 Umeå, Sweden
    • Greta Musteikyte - Institute of Biotechnology, Life Sciences Center, Vilnius University, LT-10257 Vilnius, Lithuania
    • Vytautas Smirnovas - Institute of Biotechnology, Life Sciences Center, Vilnius University, LT-10257 Vilnius, Lithuania
    • Massimo Stefani - Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50134 Florence, Italy
  • Author Contributions

    M.L., H.C., I.A.I., J.P., and Ž.M.S. contributed equally. M.S., M.B., and L.A.M.-R. conceived and designed the work. L.A.M.-R., M.L., M.S., M.B., I.A.I., and H.C. wrote the manuscript. M.L. performed all experiments with neuroblastoma cells. H.C. performed OleA binding experiments. H.C., J.P., and S.G.A. performed in vitro characterizations of the amyloid fibrillation. J.P. measured the length of the amyloid fibrils. I.A.I. conducted the conceptualization, formal analysis, methodology, data curation, validation, and visualization. Ž.M.S. performed the molecular dynamic simulation and analysis. G.M. and V.S. prepared the polypeptide samples. All coauthors discussed and commented on the manuscript.

  • Notes
    The authors declare no competing financial interest.

Acknowledgments

Click to copy section linkSection link copied!

We thank Professor Rakez Kayed, University of Texas, USA, for the gift of amyloid specific antibodies. We acknowledge the Biochemical Imaging Center at Umea University and the National Microscopy Infrastructure (NMI) (VR-RFI 2016-00968) for the use of the microscope. Research is supported by the Swedish Medical Research Council (2019-01232), Forskningsstrategiska medel, Medical Faculty, Umea University and Insamlingsstiftelsen, Umeå for LAM-R, and Research Council of Lithuania (No. S-SEN-20-3) for V.S. and ANCC-COOP/Airalzh ONLUS (Reg. No. 0043966.30-10-359 2014-u) through University of Florence (D.R.595/2016) for M.L. High-performance computing at the University of Rijeka is supported by the European Fund for Regional Development (ERDF) and by the Ministry of Science, Education and Sports of the Republic of Croatia under the project number RC.2.2.06-000.

Abbreviations

Click to copy section linkSection link copied!
AD

Alzheimer’s disease

AFM

atomic force miscroscopy

CD

circular dichroism

FRET

fluorescence resonance energy transfer

MD

molecular dynamics

OleA

oleuropein aglycone

PD

Parkinson’s disease

ROS

reactive oxidative species

RMSD

root-mean-square deviation

ThT

thioflavin-T

References

Click to copy section linkSection link copied!

This article references 69 other publications.

  1. 1
    Akiyama, H., Barger, S., Barnum, S., Bradt, B., Bauer, J., Cole, G. M., Cooper, N. R., Eikelenboom, P., Emmerling, M., Fiebich, B. L. (2000) Inflammation and Alzheimer’s disease. Neurobiol. Aging 21 (3), 383– 421,  DOI: 10.1016/S0197-4580(00)00124-X
    Google Scholar
    1
    Inflammation and Alzheimer's disease
    Akiyama, H.; Barger, S.; Barnum, S.; Bradt, B.; Bauer, J.; Cole, G. M.; Cooper, N. R.; Eikelenboom, P.; Emmerling, M.; Fiebich, B. L.; Finch, C. E.; Frautschy, S.; Griffin, W. S. T.; Hampel, H.; Hull, M.; Landreth, G.; Lue, L.-F.; Mrak, R.; Mackenzie, I. R.; McGeer, P. L.; O'Banion, M. K.; Pachter, J.; Pasinetti, G.; Plata-Salaman, C.; Rogers, J.; Rydel, R.; Shen, Y.; Streit, W.; Strohmeyer, R.; Tooyoma, I.; Van Muiswinkel, F. L.; Veerhuis, R.; Walker, D.; Webster, S.; Wegrzyniak, B.; Wenk, G.; Wyss-Coray, T.
    Neurobiology of Aging (2000), 21 (3), 383-421CODEN: NEAGDO; ISSN:0197-4580. (Elsevier Science Inc.)
    A review, with 636 refs. Inflammation clearly occurs in pathol. vulnerable regions of the Alzheimer's disease (AD) brain, and it does so with the full complexity of local peripheral inflammatory responses. In the periphery, degenerating tissue and the deposition of highly insol. abnormal materials are classical stimulants of inflammation. Likewise, in the AD brain damaged neurons and neurites and highly insol. amyloid β peptide deposits and neurofibrillary tangles provide obvious stimuli for inflammation. Because these stimuli are discrete, microlocalized, and present from early preclin. to terminal stages of AD, local upregulation of complement, cytokines, acute-phase reactants, and other inflammatory mediators is also discrete, microlocalized, and chronic. Cumulated over many years, direct and bystander damage from AD inflammatory mechanisms is likely to exacerbate the very pathogenic processes that gave rise to it. Thus, animal models and clin. studies, although still in their infancy, strongly suggest that AD inflammation contributes to AD pathogenesis. By better understanding AD inflammatory and immunoregulatory processes, it should be possible to develop anti-inflammatory approaches that may not cure AD but will likely help slow the progression or delay the onset of this devastating disorder.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXktVSmt74%253D&md5=409a0ca2920ef2cba12474cb7d05f4aa
  2. 2
    Hardy, J. and Selkoe, D. J. (2002) The Amyloid Hypothesis of Alzheimer’ s Disease: Progress and Problems on the Road to Therapeutics. Science 297 (5580), 353,  DOI: 10.1126/science.1072994
    Google Scholar
    2
    The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics
    Hardy, John; Selkoe, Dennis J.
    Science (Washington, DC, United States) (2002), 297 (5580), 353-356CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    A review. It has been more than 10 yr since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused by deposition of amyloid β-peptide (Aβ) in plaques in brain tissue. According to the amyloid hypothesis, accumulation of Aβ in the brain is the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary tangles contg. tau protein, is proposed to result from an imbalance between Aβ prodn. and Aβ clearance.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xls1Cju7s%253D&md5=f7b8db1bc6f13e85f887b73f3042e86e
  3. 3
    Zhu, S., Wang, J., Zhang, Y., He, J., Kong, J., Wang, J.-F., and Li, X.-M. (2017) The Role of Neuroinflammation and Amyloid in Cognitive Impairment in an APP/PS1 Transgenic Mouse Model of Alzheimer’s Disease. CNS Neurosci. Ther. 23 (4), 310– 320,  DOI: 10.1111/cns.12677
    Google Scholar
    3
    The role of neuroinflammation and amyloid in cognitive impairment in an APP/PS1 transgenic mouse model of Alzheimer's disease
    Zhu, Shenghua; Wang, Junhui; Zhang, Yanbo; He, Jue; Kong, Jiming; Wang, Jun-Feng; Li, Xin-Min
    CNS Neuroscience & Therapeutics (2017), 23 (4), 310-320CODEN: CNTNAB; ISSN:1755-5930. (Wiley-Blackwell)
    Aims : Both amyloid deposition and neuroinflammation appear in the early course of Alzheimer's disease (AD). However, the progression of neuroinflammation and its relationship with amyloid deposition and behavioral changes have not been fully elucidated. A better understanding the role of neuroinflammation in AD might extend our current knowledge to therapeutic intervention possibilities. Methods : This study systematically characterized changes in behavioral abnormalities in APP/PS1 transgenic mice. Brain pathol. measures were performed in post-mortem brain tissues of mice from 2 to 22 mo. Results : APP/PS1 mice exhibited significant memory deficits from 5 mo old, which were aggravated at the later stage of life. However, the degree of memory impairments reached a plateau at 12 mo. An early appearance of amyloid plaques was at 3 mo with a linear increase throughout the disease course. CD11b-pos. microglia and glial fibrillary acidic protein-(GFAP) pos. astrocytes were first detected at 3 mo with a close assocn. with amyloid plaques. Yet, the rate of changes in glial activation slowed down from 12 mo despite the steady increase in Aβ. Conclusion : These findings provided evidence that neuroinflammation might be involved in the development and progression of cognitive deficits in APP/PS1 mice, suggesting novel intervention and prevention strategies for AD.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXksFaktr8%253D&md5=34feee5613ff847c8e2615f444238bdc
  4. 4
    Demuro, A., Mina, E., Kayed, R., Milton, S. C., Parker, I., and Glabe, C. G. (2005) Calcium Dysregulation and Membrane Disruption as a Ubiquitous Neurotoxic Mechanism of Soluble Amyloid Oligomers. J. Biol. Chem. 280 (17), 17294– 17300,  DOI: 10.1074/jbc.M500997200
    Google Scholar
    4
    Calcium Dysregulation and Membrane Disruption as a Ubiquitous Neurotoxic Mechanism of Soluble Amyloid Oligomers
    Demuro, Angelo; Mina, Erene; Kayed, Rakez; Milton, Saskia C.; Parker, Ian; Glabe, Charles G.
    Journal of Biological Chemistry (2005), 280 (17), 17294-17300CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
    Increasing evidence suggests that amyloid peptides assocd. with a variety of degenerative diseases induce neurotoxicity in their intermediate oligomeric state, rather than as monomers or fibrils. To test this hypothesis and investigate the possible involvement of Ca2+ signaling disruptions in amyloid-induced cytotoxicity, the authors made homogeneous prepns. of disease-related amyloids (Aβ, prion, islet amyloid polypeptide, polyglutamine, and lysozyme) in various aggregation states and tested their actions on fluo-3-loaded SH-SY5Y cells. Application of oligomeric forms of all amyloids tested (0.6-6 μg ml-1) rapidly (∼5 s) elevated intracellular Ca2+, whereas equiv. amts. of monomers and fibrils did not. Ca2+ signals evoked by Aβ42 oligomers persisted after depletion of intracellular Ca2+ stores, and small signals remained in Ca2+-free medium, indicating contributions from both extracellular and intracellular Ca2+ sources. The increased membrane permeability to Ca2+ cannot be attributed to activation of endogenous Ca2+ channels, because responses were unaffected by the potent Ca2+-channel blocker cobalt (20 μm). Instead, observations that Aβ42 and other oligomers caused rapid cellular leakage of anionic fluorescent dyes point to a generalized increase in membrane permeability. The resulting unregulated flux of ions and mols. may provide a common mechanism for oligomer-mediated toxicity in many amyloidogenic diseases, with dysregulation of Ca2+ ions playing a crucial role because of their strong trans-membrane concn. gradient and involvement in cell dysfunction and death.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjsFOguro%253D&md5=bbecbaadfc5f74d42bd09f2cddcf5763
  5. 5
    Perry, V. H., Nicoll, J. A. R., and Holmes, C. (2010) Microglia in Neurodegenerative Disease. Nat. Rev. Neurol. 6 (4), 193– 201,  DOI: 10.1038/nrneurol.2010.17
    Google Scholar
    5
    Microglia in neurodegenerative disease
    Perry V Hugh; Nicoll James A R; Holmes Clive
    Nature reviews. Neurology (2010), 6 (4), 193-201 ISSN:.
    Microglia, the resident macrophages of the CNS, are exquisitely sensitive to brain injury and disease, altering their morphology and phenotype to adopt a so-called activated state in response to pathophysiological brain insults. Morphologically activated microglia, like other tissue macrophages, exist as many different phenotypes, depending on the nature of the tissue injury. Microglial responsiveness to injury suggests that these cells have the potential to act as diagnostic markers of disease onset or progression, and could contribute to the outcome of neurodegenerative diseases. The persistence of activated microglia long after acute injury and in chronic disease suggests that these cells have an innate immune memory of tissue injury and degeneration. Microglial phenotype is also modified by systemic infection or inflammation. Evidence from some preclinical models shows that systemic manipulations can ameliorate disease progression, although data from other models indicates that systemic inflammation exacerbates disease progression. Systemic inflammation is associated with a decline in function in patients with chronic neurodegenerative disease, both acutely and in the long term. The fact that diseases with a chronic systemic inflammatory component are risk factors for Alzheimer disease implies that crosstalk occurs between systemic inflammation and microglia in the CNS.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3c3kslyntw%253D%253D&md5=efb215a8a737c924905e7aa04a5b6706
  6. 6
    Paradisi, S., Sacchetti, B., Balduzzi, M., Gaudi, S., and Malchiodi-Albedi, F. (2004) Astrocyte Modulation of In Vitro β-Amyloid Neurotoxicity. Glia 46 (3), 252– 260,  DOI: 10.1002/glia.20005
    Google Scholar
    6
    Astrocyte modulation of in vitro beta-amyloid neurotoxicity
    Paradisi Silvia; Sacchetti Benedetto; Balduzzi Maria; Gaudi Simona; Malchiodi-Albedi Fiorella
    Glia (2004), 46 (3), 252-60 ISSN:0894-1491.
    In Alzheimer's disease brain, beta-amyloid (Abeta) deposition is accompanied by astrocyte activation, whose role in the pathogenesis of the disease is still unclear. To explore the subject, we compared Abeta neurotoxicity in pure hippocampal cultures and neuronal-astrocytic cocultures, where astrocytes conditioned neurons but were not in contact with them or Abeta. In the presence of astrocytes, neurons were protected from Abeta neurotoxicity. Neuritic dystrophy was reduced, synapses were partially preserved, and apoptosis was contrasted. The protection disappeared when astrocytes were also treated with Abeta, suggesting that Abeta-astrocyte interaction is deleterious for neurons. This was supported by comparing Abeta neurotoxicity in pure neurons and neurons grown on astrocytes. In this case, where astrocytes were also in contact with Abeta, neuritic damage was enhanced and expression of synaptic vesicle proteins decreased. Our results suggest that astrocytes can protect neurons from Abeta neurotoxicity, but when they interact with Abeta, the protection is undermined and neurotoxicity enhanced.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2c7lsVerug%253D%253D&md5=d8fce7b7e08c280b10ed9f8b444a8936
  7. 7
    Eikelenboom, P., Hoozemans, J. J., Veerhuis, R., van Exel, E., Rozemuller, A. J., and van Gool, W. A. (2012) Whether, When and How Chronic Inflammation Increases the Risk of Developing Late-onset Alzheimer’s Disease. Alzheimer's Res. Ther. 4 (3), 15– 15,  DOI: 10.1186/alzrt118
    Google Scholar
    7
    Whether, when and how chronic inflammation increases the risk of developing late-onset Alzheimer's disease
    Eikelenboom, Piet; Hoozemans, Jeroen J. M.; Veerhuis, Rob; van Exel, Eric; Rozemuller, Annemieke J. M.; van Gool, Willem A.
    Alzheimer's Research & Therapy (2012), 4 (3), 15CODEN: ARTLCD; ISSN:1758-9193. (BioMed Central Ltd.)
    A review. Neuropathol. studies have revealed the presence of a broad variety of inflammation-related proteins (complement factors, acute-phase proteins, pro-inflammatory cytokines) in Alzheimer's disease (AD) brains. These constituents of innate immunity are involved in several crucial pathogenic events of the underlying pathol. cascade in AD and recent studies have shown that innate immunity is involved in the etiol. of late-onset AD. Genome-wide assocn. studies have demonstrated gene loci that are linked to the complement system. Neuropathol. and exptl. studies indicate that fibrillar amyloid-β (Aβ) can activate the innate immunity-related CD14 and Toll-like receptor signaling pathways of glial cells for pro-inflammatory cytokine prodn. The prodn. capacity of this pathway is under genetic control and offspring with a parental history of late-onset AD have a higher prodn. capacity for pro-inflammatory cytokines. The activation of microglia by fibrillar Aβ deposits in the early preclin. stages of AD can make the brain susceptible later on for a second immune challenge leading to enhanced prodn. of pro-inflammatory cytokines. An example of a second immune challenge could be systemic inflammation in patients with preclin. AD. Prospective epidemiol. studies show that elevated serum levels of acute phase reactants can be considered as a risk factor for AD. Clin. studies suggest that peripheral inflammation increases the risk of dementia, esp. in patients with preexistent cognitive impairment and accelerates further deterioration in demented patients. The view that peripheral inflammation can increase the risk of dementia in older people provides scope for prevention.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xpt1ajurw%253D&md5=a2a92116ef2fb0e70170b35ee945713c
  8. 8
    Lim, S., Chun, Y., Lee, J. S., and Lee, S.-J. (2016) Neuroinflammation in Synucleinopathies. Brain Pathol. 26 (3), 404– 409,  DOI: 10.1111/bpa.12371
    Google Scholar
    8
    Neuroinflammation in Synucleinopathies
    Lim Somin; Chun Yewon; Lee Jun Sung; Lee Seung-Jae
    Brain pathology (Zurich, Switzerland) (2016), 26 (3), 404-9 ISSN:.
    The causes of most neurodegenerative diseases are attributed to multiple genetic and environmental factors interacting with one another. Above all, inflammation in the nervous system has been implicated in many neurodegenerative diseases. Still, the roles of neuroinflammation in disease mechanisms and the triggers of inflammatory responses in disease-inflicted brain tissues seem to remain unclear. This review will examine previous studies that had been done from genetic, pathological and epidemiological perspectives. These studies assess the involvement of neuroinflammation in synucleinopathies, a group of neurodegenerative diseases that are characterized by deposition of α-synuclein aggregates such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. The review will also discuss the role of α-synuclein aggregates in triggering inflammatory responses from glial cells. It is expected that a precise assessment of the roles and mechanisms of neuroinflammation in neurodegenerative diseases will pave the way for the development of disease-modifying drugs.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28jmslyjsw%253D%253D&md5=0db4eb9a45b73151df154d7ce22d55a9
  9. 9
    Wang, C., Iashchishyn, I. A., Pansieri, J., Nystrom, S., Klementieva, O., Kara, J., Horvath, I., Moskalenko, R., Rofougaran, R., Gouras, G. (2018) S100A9-Driven Amyloid-Neuroinflammatory Cascade in Traumatic Brain Injury as a Precursor State for Alzheimer’s Disease. Sci. Rep. 8, 12836,  DOI: 10.1038/s41598-018-31141-x
    Google Scholar
    9
    S100A9-Driven Amyloid-Neuroinflammatory Cascade in Traumatic Brain Injury as a Precursor State for Alzheimer's Disease
    Wang Chao; Iashchishyn Igor A; Pansieri Jonathan; Kara John; Horvath Istvan; Moskalenko Roman; Rofougaran Reza; Morozova-Roche Ludmilla A; Iashchishyn Igor A; Nystrom Sofie; Klementieva Oxana; Gouras Gunnar; Moskalenko Roman; Kovacs Gabor G; Shankar S K
    Scientific reports (2018), 8 (1), 12836 ISSN:.
    Pro-inflammatory and amyloidogenic S100A9 protein is an important contributor to Alzheimer's disease (AD) pathology. Traumatic brain injury (TBI) is viewed as a precursor state for AD. Here we have shown that S100A9-driven amyloid-neuroinflammatory cascade was initiated in TBI and may serve as a mechanistic link between TBI and AD. By analyzing the TBI and AD human brain tissues, we demonstrated that in post-TBI tissues S100A9, produced by neurons and microglia, becomes drastically abundant compared to Aβ and contributes to both precursor-plaque formation and intracellular amyloid oligomerization. Conditions implicated in TBI, such as elevated S100A9 concentration, acidification and fever, provide strong positive feedback for S100A9 nucleation-dependent amyloid formation and delay in its proteinase clearance. Consequently, both intracellular and extracellular S100A9 oligomerization correlated with TBI secondary neuronal loss. Common morphology of TBI and AD plaques indicated their similar initiation around multiple aggregation centers. Importantly, in AD and TBI we found S100A9 plaques without Aβ. S100A9 and Aβ plaque pathology was significantly advanced in AD cases with TBI history at earlier age, signifying TBI as a risk factor. These new findings highlight the detrimental consequences of prolonged post-TBI neuroinflammation, which can sustain S100A9-driven amyloid-neurodegenerative cascade as a specific mechanism leading to AD development.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3c3itlOitw%253D%253D&md5=f4623ac4ea93ef3ab98aa20a3c70f5cf
  10. 10
    Horvath, I., Iashchishyn, I. A., Moskalenko, R. A., Wang, C., Warmlander, S. K. T. S., Wallin, C., Graslund, A., Kovacs, G. G., and Morozova-Roche, L. A. (2018) Co-aggregation of Pro-inflammatory S100A9 with Alpha-Synuclein in Parkinson’s Disease: Ex Vivo and In Vitro Studies. J. Neuroinflammation 15, 172,  DOI: 10.1186/s12974-018-1210-9
    Google Scholar
    10
    Co-aggregation of pro-inflammatory S100A9 with α-synuclein in Parkinson's disease: ex vivo and in vitro studies
    Horvath, Istvan; Iashchishyn, Igor A.; Moskalenko, Roman A.; Wang, Chao; Waermlaender, Sebastian K. T. S.; Wallin, Cecilia; Graeslund, Astrid; Kovacs, Gabor G.; Morozova-Roche, Ludmilla A.
    Journal of Neuroinflammation (2018), 15 (), 172/1-172/16CODEN: JNOEB3; ISSN:1742-2094. (BioMed Central Ltd.)
    Background: Chronic neuroinflammation is a hallmark of Parkinson's disease (PD) pathophysiol., assocd. with increased levels of pro-inflammatory factors in PD brain tissues. The pro-inflammatory mediator and highly amyloidogenic protein S100A9 is involved in the amyloid-neuroinflammatory cascade in Alzheimer's disease. This is the first report on the co-aggregation of α-synuclein (α-syn) and S100A9 both in vitro and ex vivo in PD brain. Methods: Single and sequential immunohistochem., immunofluorescence, scanning electron and at. force (AFM) microscopies were used to analyze the ex vivo PD brain tissues for S100A9 and α-syn location and aggregation. In vitro studies revealing S100A9 and α-syn interaction and co-aggregation were conducted by NMR, CD, Thioflavin-T fluorescence, AFM, and surface plasmon resonance methods. Results: Co-localized and co-aggregated S100A9 and α-syn were found in 20% Lewy bodies and 77% neuronal cells in the substantia nigra; both proteins were also obsd. in Lewy bodies in PD frontal lobe (Braak stages 4-6). Lewy bodies were characterized by ca. 10-23 μm outer diam., with S100A9 and α-syn being co-localized in the same lamellar structures. S100A9 was also detected in neurons and blood vessels of the aged patients without PD, but in much lesser extent. In vitro S100A9 and α-syn were shown to interact with each other via the α-syn C-terminus with an apparent dissocn. const. of ca. 5 μM. Their co-aggregation occurred significantly faster and led to formation of larger amyloid aggregates than the self-assembly of individual proteins. S100A9 amyloid oligomers were more toxic than those of α-syn, while co-aggregation of both proteins mitigated the cytotoxicity of S100A9 oligomers. Conclusions: We suggest that sustained neuroinflammation promoting the spread of amyloidogenic S100A9 in the brain tissues may trigger the amyloid cascade involving α-syn and S100A9 and leading to PD, similar to the effect of S100A9 and Aβ co-aggregation in Alzheimer's disease. The finding of S100A9 involvement in PD may open a new avenue for therapeutic interventions targeting S100A9 and preventing its amyloid self-assembly in affected brain tissues.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFWgurrK&md5=713ff8fce99cbbd976b097ec98515dbc
  11. 11
    Wang, C., Klechikov, A. G., Gharibyan, A. L., Wärmländer, S. K. T. S., Jarvet, J., Zhao, L., Jia, X., Narayana, V. K., Shankar, S. K., Olofsson, A. (2014) The Role of Pro-inflammatory S100A9 in Alzheimer’s Disease Amyloid-neuroinflammatory Cascade. Acta Neuropathol. 127 (4), 507– 522,  DOI: 10.1007/s00401-013-1208-4
    Google Scholar
    11
    The role of pro-inflammatory S100A9 in Alzheimer's disease amyloid-neuroinflammatory cascade
    Wang, Chao; Klechikov, Alexey G.; Gharibyan, Anna L.; Waermlaender, Sebastian K. T. S.; Jarvet, Juri; Zhao, Lina; Jia, Xueen; Shankar, S. K.; Olofsson, Anders; Braennstroem, Thomas; Mu, Yuguang; Graeslund, Astrid; Morozova-Roche, Ludmilla A.
    Acta Neuropathologica (2014), 127 (4), 507-522CODEN: ANPTAL; ISSN:0001-6322. (Springer)
    Pro-inflammatory S100A9 protein is increasingly recognized as an important contributor to inflammation-related neurodegeneration. Here, we provide insights into S100A9 specific mechanisms of action in Alzheimer's disease (AD). Due to its inherent amyloidogenicity S100A9 contributes to amyloid plaque formation together with Aβ. In traumatic brain injury (TBI) S100A9 itself rapidly forms amyloid plaques, which were reactive with oligomer-specific antibodies, but not with Aβ and amyloid fibrillar antibodies. They may serve as precursor-plaques for AD, implicating TBI as an AD risk factor. S100A9 was obsd. in some hippocampal and cortical neurons in TBI, AD and non-demented aging. In vitro S100A9 forms neurotoxic linear and annular amyloids resembling Aβ protofilaments. S100A9 amyloid cytotoxicity and native S100A9 pro-inflammatory signaling can be mitigated by its co-aggregation with Aβ, which results in a variety of micron-scale amyloid complexes. NMR and mol. docking demonstrated transient interactions between native S100A9 and Aβ. Thus, abundantly present in AD brain pro-inflammatory S100A9, possessing also intrinsic amyloidogenic properties and ability to modulate Aβ aggregation, can serve as a link between the AD amyloid and neuroinflammatory cascades and as a prospective therapeutic target.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslymu7bF&md5=af7f01a5c3f6f24fc24aa907b72e9e43
  12. 12
    Pruenster, M., Vogl, T., Roth, J., and Sperandio, M. (2016) S100A8/A9: From Basic Science to Clinical Application. Pharmacol. Ther. 167, 120– 131,  DOI: 10.1016/j.pharmthera.2016.07.015
    Google Scholar
    12
    S100A8/A9: From basic science to clinical application
    Pruenster, Monika; Vogl, Thomas; Roth, Johannes; Sperandio, Markus
    Pharmacology & Therapeutics (2016), 167 (), 120-131CODEN: PHTHDT; ISSN:0163-7258. (Elsevier)
    Neutrophils and monocytes belong to the first line of immune defense cells and are recruited to sites of inflammation during infection or sterile injury. Both cells contain huge amts. of the heterodimeric protein S100A8/A9 in their cytoplasm. S100A8/A9 belongs to the Ca2 + binding S100 protein family and has recently gained a lot of interest as a crit. alarmin modulating the inflammatory response after its release (extracellular S100A8/A9) from neutrophils and monocytes. Extracellular S100A8/A9 interacts with the pattern recognition receptors Toll-like receptor 4 (TLR4) and Receptor for Advanced Glycation Endproducts (RAGE) promoting cell activation and recruitment. Besides its biol. function, S100A8/A9 (also known as myeloid related protein 8/14, MRP8/14) was identified as interesting biomarker to monitor disease activity in chronic inflammatory disorders including inflammatory bowel disease and rheumatoid arthritis. Furthermore, S100A8/A9 has been tested successfully in pre-clin. imaging studies to localize sites of infection or sterile injury. Finally, recent evidence using small mol. inhibitors for S100A8/A9 also suggests that blocking S100A8/A9 activity exerts beneficial effects on disease activity in animal models of autoimmune diseases including multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel disease. This review will provide a comprehensive and detailed overview into the structure and biol. function of S100A8/A9 and also will give an outlook in terms of diagnostic and therapeutic applications targeting S100A8/A9.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlWjurzJ&md5=99ce16a70a32600c9f393ae6bfef9b90
  13. 13
    Markowitz, J. and Carson, W. E., 3rd. (2013) Review of S100A9 Biology and Its Role in Cancer. Biochim. Biophys. Acta, Rev. Cancer 1835 (1), 100– 109,  DOI: 10.1016/j.bbcan.2012.10.003
    Google Scholar
    13
    Review of S100A9 biology and its role in cancer
    Markowitz, Joseph; Carson, William E.
    Biochimica et Biophysica Acta, Reviews on Cancer (2013), 1835 (1), 100-109CODEN: BBACEU; ISSN:0304-419X. (Elsevier B.V.)
    A review. S100A9 is a calcium binding protein with multiple ligands and post-translation modifications that is involved in inflammatory events and the initial development of the cancer cell through to the development of metastatic disease. This review has a threefold purpose: 1) describe the S100A9 structural elements important for its biol. activity, 2) describe the S100A9 biol. in the context of the immune system, and 3) illustrate the role of S100A9 in the development of malignancy via interactions with the immune system and other cellular processes.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVKqurzJ&md5=b417186ba1010bf09ea0e350e2acd708
  14. 14
    Schluesener, H. J., Kremsner, P. G., and Meyermann, R. (1998) Widespread Expression of MRP8 and MRP14 in Human Cerebral Malaria by Microglial Cells. Acta Neuropathol. 96 (6), 575– 580,  DOI: 10.1007/s004010050938
    Google Scholar
    14
    Widespread expression of MRP8 and MRP14 in human cerebral malaria by microglial cells
    Schluesener, H. J.; Kremsner, Peter G.; Meyermann, Richard
    Acta Neuropathologica (1998), 96 (6), 575-580CODEN: ANPTAL; ISSN:0001-6322. (Springer-Verlag)
    Human cerebral malaria (CM) is an often fatal infection. The cascades of signaling events resulting in tissue trauma and coma are only slowly becoming unraveled. Here the authors report that microglial cells, sensitive cellular sensors of threats to the central nervous system, in CM express the myeloid-related proteins MRP8 (S100A8) and MRP14 (S100A9), Ca2+-binding sensor proteins of activated monocytes. Surprisingly, microglial activation was widespread throughout the brain in white and gray matter and not limited to areas of petechial bleedings or sequestration of infected erythrocytes. Further, apoptosis/necrosis is prominent in CM; not only leukocytes appeared apoptotic, neurons also appeared damaged and DNA fragmentation was revealed by in situ nick translation. Thus, a prominent feature of human CM is activation of microglia, and anal. of these reactive microglia might further promote the authors' understanding of CM pathol. and guide development of future therapeutic intervention of the local reactive processes.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXmvFyitLo%253D&md5=4db5ed68a417b831c80894978e554c30
  15. 15
    Postler, E., Lehr, A., Schluesener, H., and Meyermann, R. (1997) Expression of the S-100 proteins MRP-8 and −14 in Ischemic Brain Lesions. Glia 19 (1), 27– 34,  DOI: 10.1002/(SICI)1098-1136(199701)19:1<27::AID-GLIA3>3.0.CO;2-7
    Google Scholar
    15
    Expression of the S-100 proteins MRP-8 and -14 in ischemic brain lesions
    Postler E; Lehr A; Schluesener H; Meyermann R
    Glia (1997), 19 (1), 27-34 ISSN:0894-1491.
    So far, microglial activation in cerebral ischemia has only been studied in different animal models. We have investigated the activation of microglial cells in human cerebral ischemia. As a marker for the activation of these "brain macrophages," we have used the macrophage inhibitor factor-related-proteins MRP-8 and MRP-14, which belong to the calcium binding S-100 protein family. The proteins can be detected on microglial cells in bacterial encephalitis and Alzheimer's disease but have so far not been studied in non-inflammatory diseases, in which microglial activation also occurs. Antibodies against MRP-8 and -14 detected ramified microglial cells within the first 3 days after cerebral infarction. Labeled cells were found selectively in the periinfarctional area. To support the notion that these cells belong to the locally activated resident microglial population, we studied their proliferation rate by staining the Ki-67 antigen with the antibody MIB-1. Double-labeling clearly showed that in the early phase of cerebral infarction microglial cells in the periinfarctional area express MRP-8 and -14 and also proliferate. Surprisingly, MRPs are expressed no longer than 3 days post infarction. This indicates that the activation of the resident microglia is an early step of tissue reaction after cerebral infarction. Additionally, we found evidence that microglial cells contribute to the population of phagocytes only during the first 3 days post infarction. The majority of lipid phagocytes found in the later stages are obviously recruited from the blood-borne macrophage pool.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2s7ktlGmtg%253D%253D&md5=b269af3ced945688d66f310da4d3e5dc
  16. 16
    Nagareddy, P. R., Murphy, A. J., Stirzaker, R. A., Hu, Y., Yu, S., Miller, R. G., Ramkhelawon, B., Distel, E., Westerterp, M., Huang, L.-S. (2013) Hyperglycemia Promotes Myelopoiesis and Impairs the Resolution of Atherosclerosis. Cell Metab. 17 (5), 695– 708,  DOI: 10.1016/j.cmet.2013.04.001
    Google Scholar
    16
    Hyperglycemia Promotes Myelopoiesis and Impairs the Resolution of Atherosclerosis
    Nagareddy, Prabhakara R.; Murphy, Andrew J.; Stirzaker, Roslynn A.; Hu, Yunying; Yu, Shiquing; Miller, Rachel G.; Ramkhelawon, Bhama; Distel, Emilie; Westerterp, Marit; Huang, Li-Shin; Schmidt, Ann Marie; Orchard, Trevor J.; Fisher, Edward A.; Tall, Alan R.; Goldberg, Ira J.
    Cell Metabolism (2013), 17 (5), 695-708CODEN: CMEEB5; ISSN:1550-4131. (Elsevier Inc.)
    Diabetes is a major risk factor for atherosclerosis. Although atherosclerosis is initiated by deposition of cholesterol-rich lipoproteins in the artery wall, the entry of inflammatory leukocytes into lesions fuels disease progression and impairs resoln. We show that diabetic mice have increased nos. of circulating neutrophils and Ly6-Chi monocytes, reflecting hyperglycemia-induced proliferation and expansion of bone marrow myeloid progenitors and release of monocytes into the circulation. Increased neutrophil prodn. of S100A8/S100A9, and its subsequent interaction with the receptor for advanced glycation end products on common myeloid progenitor cells, leads to enhanced myelopoiesis. Treatment of hyperglycemia reduces monocytosis, entry of monocytes into atherosclerotic lesions, and promotes regression. In patients with type 1 diabetes, plasma S100A8/S100A9 levels correlate with leukocyte counts and coronary artery disease. Thus, hyperglycemia drives myelopoiesis and promotes atherogenesis in diabetes.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnsVyqs7Y%253D&md5=ff11d96d88b7b22191ca54f90233b5d4
  17. 17
    Ma, L.-P., Haugen, E., Ikemoto, M., Fujita, M., Terasaki, F., and Fu, M. (2012) S100A8/A9 Complex as a New Biomarker in Prediction of Mortality in Elderly Patients with Severe Heart Failure. Int. J. Cardiol. 155 (1), 26– 32,  DOI: 10.1016/j.ijcard.2011.01.082
    Google Scholar
    17
    S100A8/A9 complex as a new biomarker in prediction of mortality in elderly patients with severe heart failure
    Ma Li-Ping; Haugen Espen; Ikemoto Masaki; Fujita Masatoshi; Terasaki Fumio; Fu Michael
    International journal of cardiology (2012), 155 (1), 26-32 ISSN:.
    BACKGROUND: S100A8/A9 complex is a new inflammation-related protein and has a positive correlation with C-reaction protein level. However its role in chronic heart failure (CHF) remains unclear. METHODS AND RESULTS: Circulating levels of S100A8/A9 complex and other biomarkers (IL-6, IL-8, TNF-α, and BNP) were measured in CHF (n = 54) and hypertensive without CHF (n = 31) as well as healthy subjects (n = 23), with follow up to 1480 days. During follow-up, cumulative mortality rate for CHF patients was 63%. Plasma levels of S100A8/A9 complex, IL-6, IL-8 and TNF-α were significantly higher in CHF than the hypertensive patients and healthy subjects. A significant positive correlation was found between S100A8/A9 complex and IL-6 and IL-8 respectively. Cox regression analysis showed that IL-6 and IL-8 were predictors for mortality for 6 months, and S100A8/A9 complex, IL-6, IL-8 and age were predictors for mortality for one year whereas BNP, TNF-α, IL-6 and IL-8 remained predictors for mortality for two years. A combination of S100A8/A9 complex and IL-6 provided powerful predictive value in mortality for both 6 and 12 months. CONCLUSIONS: S100A8/A9 complex is a useful biomarker as a predictor for one year mortality and its combination with IL-6 is able to provide additive prognostic information in this vulnerable heart failure population in the elderly.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC383gsFyiuw%253D%253D&md5=9e31f29e08d75738e968ef7fbe218022
  18. 18
    Swindell, W. R., Johnston, A., Xing, X., Little, A., Robichaud, P., Voorhees, J. J., Fisher, G., and Gudjonsson, J. E. (2013) Robust Shifts in S100A9 Expression with Aging: A Novel Mechanism for Chronic Inflammation. Sci. Rep. 3 (1), 1215,  DOI: 10.1038/srep01215
    Google Scholar
    18
    Robust shifts in S100a9 expression with aging: a novel mechanism for chronic inflammation
    Swindell, William R.; Johnston, Andrew; Xing, Xianying; Little, Andrew; Robichaud, Patrick; Voorhees, John J.; Fisher, Gary; Gudjonsson, Johann E.
    Scientific Reports (2013), 3 (), 1215, 13 pp.CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)
    The S100a8 and S100a9 genes encode a pro-inflammatory protein (calgranulin) that has been implicated in multiple diseases. However, involvement of S100a8/a9 in the basic mechanisms of intrinsic aging has not been established. In this study, we show that shifts in the abundance of S100a8 and S100a9 mRNA are a robust feature of aging in mammalian tissues, involving a range of cell types including the central nervous system. To identify transcription factors that control S100a9 expression, we performed a large-scale transcriptome anal. of 62 mouse and human cell types. We identified cell type-specific trends, as well as robust assocns. linking S100a9 coexpression to elevated frequency of ETS family motifs and in particular, to motifs recognized by the transcription factor SPI/PU.1. Sparse occurrence of SATB1 motifs was also a strong predictor of S100a9 coexpression. These findings offer support for a novel mechanism by which a SPI1/PU.1-S100a9 axis sustains chronic inflammation during aging.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXpvFWjt74%253D&md5=8ff1b1f10a81db6c7d8496626fc2c72b
  19. 19
    Iashchishyn, I. A., Sulskis, D., Nguyen Ngoc, M., Smirnovas, V., and Morozova-Roche, L. A. (2017) Finke–Watzky Two-Step Nucleation–Autocatalysis Model of S100A9 Amyloid Formation: Protein Misfolding as “Nucleation” Event. ACS Chem. Neurosci. 8 (10), 2152– 2158,  DOI: 10.1021/acschemneuro.7b00251
    Google Scholar
    19
    Finke-Watzky Two-Step Nucleation-Autocatalysis Model of S100A9 Amyloid Formation: Protein Misfolding as "Nucleation" Event
    Iashchishyn, Igor A.; Sulskis, Darius; Nguyen Ngoc, Mai; Smirnovas, Vytautas; Morozova-Roche, Ludmilla A.
    ACS Chemical Neuroscience (2017), 8 (10), 2152-2158CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
    Quant. kinetic anal. is crit. for understanding amyloid mechanisms. Here, we demonstrate the application of the generic Finke-Watzky (F-W; 1997, 2008) 2-step nucleation-autocatalytic growth model to concn.-dependent amyloid kinetics of proinflammatory α-helical S100A9 protein/calgranulin B at pH 7.4 and temps. of 37 and 42°. The model is based on 2 pseudo-elementary reaction steps applied without further anal. constraints and its treatment of S100A9 amyloid self-assembly demonstrates that initial misfolding and β-sheet formation, defined as a "nucleation" step, spontaneously takes place within individual S100A9 mols. at a higher rate than the subsequent fibrillar growth. The latter, described as an autocatalytic process, will proceed if misfolded amyloid-prone S100A9 is populated on a macroscopic time scale. Short lengths of S100A9 fibrils were consistent with the F-W model. The anal. of fibrillar length distribution by the Bekker-Doering model demonstrated independently that such distribution was solely detd. by slow fibril growth and that there was no fragmentation or secondary pathways decreasing fibrillar length.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1Cltb3P&md5=9e6270edc1a9e7e2d0277ab483d7f14f
  20. 20
    Yanamandra, K., Alexeyev, O., Zamotin, V., Srivastava, V., Shchukarev, A., Brorsson, A.-C., Tartaglia, G. G., Vogl, T., Kayed, R., Wingsle, G. (2009) Amyloid Formation by the Pro-inflammatory S100A8/A9 Proteins in the Ageing Prostate. PLoS One 4 (5), e5562– e5562,  DOI: 10.1371/journal.pone.0005562
    Google Scholar
    There is no corresponding record for this reference.
  21. 21
    Eremenko, E., Ben-Zvi, A., Morozova-Roche, L. A., and Raveh, D. (2013) Aggregation of Human S100A8 and S100A9 Amyloidogenic Proteins Perturbs Proteostasis in a Yeast Model. PLoS One 8 (3), e58218  DOI: 10.1371/journal.pone.0058218
    Google Scholar
    21
    Aggregation of human S100A8 and S100A9 amyloidogenic proteins perturbs proteostasis in a yeast model
    Eremenko, Ekaterina; Ben-Zvi, Anat; Morozova-Roche, Ludmilla A.; Raveh, Dina
    PLoS One (2013), 8 (3), e58218CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
    Amyloid aggregates of the calcium-binding EF-hand proteins S100A8 and S100A9 have been found in the corpora amylacea of patients with prostate cancer and may play a role in carcinogenesis. Here, the authors present a novel model system using the yeast Saccharomyces cerevisiae to study human S100A8 and S100A9 aggregation and toxicity. They found that S100A8, S100A9 and S100A8/9 cotransfomants form SDS-resistant non-toxic aggregates in yeast cells. Using fluorescently tagged proteins, the authors showed that S100A8 and S100A9 accumulate in foci. After prolonged induction, S100A8 foci localized to the cell vacuole, whereas the S100A9 foci remained in the cytoplasm when present alone, but entered the vacuole in cotransformants. Biochem. anal. of the proteins indicated that S100A8 and S100A9 alone or coexpressed together form amyloid-like aggregates in yeast. Expression of S100A8 and S100A9 in wild-type yeast did not affect cell viability, but these proteins were toxic when expressed on a background of unrelated metastable temp.-sensitive mutant proteins, Cdc53-1p, Cdc34-2p, Srp1-31p and Sec27-1p. This finding suggests that the expression and aggregation of S100A8 and S100A9 may limit the capacity of the cellular proteostasis machinery. To test this hypothesis, the authors screened a set of chaperone deletion mutants and found that reducing the levels of the heat-shock proteins Hsp104p and Hsp70p was sufficient to induce S100A8 and S100A9 toxicity. This result indicates that the chaperone activity of the Hsp104/Hsp70 bichaperone system in wild type cells is sufficient to reduce S100A8 and S100A9 amyloid toxicity and preserve cellular proteostasis. Expression of human S100A8 and S100A9 in yeast thus provides a novel model system for the study of the interaction of amyloid deposits with the proteostasis machinery.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXktlWjsrg%253D&md5=adb676af9433824aad66ff794da89062
  22. 22
    Horvath, I., Jia, X., Johansson, P., Wang, C., Moskalenko, R., Steinau, A., Forsgren, L., Wågberg, T., Svensson, J., Zetterberg, H., and Morozova-Roche, L. A. (2016) Pro-inflammatory S100A9 Protein as a Robust Biomarker Differentiating Early Stages of Cognitive Impairment in Alzheimer’s Disease. ACS Chem. Neurosci. 7 (1), 34– 39,  DOI: 10.1021/acschemneuro.5b00265
    Google Scholar
    22
    Pro-inflammatory S100A9 Protein as a Robust Biomarker Differentiating Early Stages of Cognitive Impairment in Alzheimer's Disease
    Horvath, Istvan; Jia, Xueen; Johansson, Per; Wang, Chao; Moskalenko, Roman; Steinau, Andreas; Forsgren, Lars; Waagberg, Thomas; Svensson, Johan; Zetterberg, Henrik; Morozova-Roche, Ludmilla A.
    ACS Chemical Neuroscience (2016), 7 (1), 34-39CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
    Pro-inflammatory protein S100A9 was established as a biomarker of dementia progression and compared with others such as Aβ1-42 and tau-proteins. CSF samples from 104 stringently diagnosed individuals divided into five subgroups were analyzed, including nondemented controls, stable mild cognitive impairment (SMCI), mild cognitive impairment due to Alzheimer's disease (MCI-AD), Alzheimer's disease (AD), and vascular dementia (VaD) patients. ELISA, dot-blotting, and electrochem. impedance spectroscopy were used as research methods. The S100A9 and Aβ1-42 levels correlated with each other: their CSF content decreased already at the SMCI stage and declined further under MCI-AD, AD, and VaD conditions. Immunohistochem. anal. also revealed involvement of both Aβ1-42 and S100A9 in the amyloid-neuroinflammatory cascade already during SMCI. Tau proteins were not yet altered in SMCI; however their contents increased during MCI-AD and AD, diagnosing later dementia stages. Thus, four biomarkers together, reflecting different underlying pathol. causes, can accurately differentiate dementia progression and also distinguish AD from VaD.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslyktbjM&md5=9a2362b63b01d23b69f4dd2b4e6c5c88
  23. 23
    Stefani, M. and Rigacci, S. (2014) Beneficial Properties of Natural Phenols: Highlight on Protection Against Pathological Conditions Associated with Amyloid Aggregation. BioFactors 40 (5), 482– 493,  DOI: 10.1002/biof.1171
    Google Scholar
    23
    Beneficial properties of natural phenols: Highlight on protection against pathological conditions associated with amyloid aggregation
    Stefani, Massimo; Rigacci, Stefania
    BioFactors (2014), 40 (5), 482-493CODEN: BIFAEU; ISSN:1872-8081. (Wiley-Blackwell)
    A review. Mediterranean and Asian diets are currently considered as the most healthy traditional feeding habits effective against risk of age-assocd., particularly cardiovascular and neurodegenerative, diseases. A common feature of these two regimens is the abundance of foods and beverages of plant origin (green tea, extra virgin olive oil, red wine, spices, berries, and arom. herbs) that are considered responsible for the obsd. beneficial effects. Epidemiol. data suggest that the phenolic component remarkably enriched in these foods plays an important role in reducing the incidence of amyloid diseases, pathol. conditions assocd. to tissue deposition of toxic protein aggregates responsible for progressive functional deterioration. Great effort is being spent to provide knowledge on the effects of several natural phenols in this context, moving from the test tube to animal models and, more slowly, to the patient's bed. An emerging feature that makes these mols. increasingly attractive for amyloid disease prevention and therapy is their wide spectrum of activity: recent pieces of evidence suggest that they can inhibit the prodn. of amyloidogenic peptides from precursors, increase antioxidant enzyme activity, activate autophagy and reduce inflammation. Our concept should than shift from considering natural phenols simply as antioxidants or, at the best, as amyloid aggregation inhibitors, to describing them as potentially multitargeting drugs. A main concern is the low bioavailability of such compds. and efforts aimed at improving it are underway, with encapsulation strategies being the most promising ones. © 2014 BioFactors, 40(5):482-493, 2014.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVWnsLfM&md5=6fe575d1bd7e30a74c54978a209a92f9
  24. 24
    Leri, M., Scuto, M., Ontario, M. L., Calabrese, V., Calabrese, E. J., Bucciantini, M., and Stefani, M. (2020) Healthy Effects of Plant Polyphenols: Molecular Mechanisms. Int. J. Mol. Sci. 21 (4), 1250,  DOI: 10.3390/ijms21041250
    Google Scholar
    24
    Healthy effects of plant polyphenols molecular mechanisms
    Leri, Manuela; Scuto, Maria; Ontario, Maria Laura; Calabrese, Vittorio; Calabrese, Edward J.; Bucciantini, Monica; Stefani, Massimo
    International Journal of Molecular Sciences (2020), 21 (4), 1250CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)
    The increasing extension in life expectancy of human beings in developed countries is accompanied by a progressively greater rate of degenerative diseases assocd. with lifestyle and aging, most of which are still waiting for effective, not merely symptomatic, therapies. Accordingly, at present, the recommendations aimed at reducing the prevalence of these conditions in the population are limited to a safer lifestyle including phys./mental exercise, a reduced caloric intake, and a proper diet in a convivial environment. The claimed health benefits of the Mediterranean and Asian diets have been confirmed in many clin. trials and epidemiol. surveys. These diets are characterized by several features, including low meat consumption, the intake of oils instead of fats as lipid sources, moderate amts. of red wine, and significant amts. of fresh fruit and vegetables. In particular, the latter have attracted popular and scientific attention for their content, though in reduced amts., of a no. of mols. increasingly investigated for their healthy properties. Among the latter, plant polyphenols have raised remarkable interest in the scientific community; in fact, several clin. trials have confirmed that many health benefits of the Mediterranean/Asian diets can be traced back to the presence of significant amts. of these mols., even though, in some cases, contradictory results have been reported, which highlights the need for further investigation. In light of the results of these trials, recent research has sought to provide information on the biochem., mol., epigenetic, and cell biol. modifications by plant polyphenols in cell, organismal, animal, and human models of cancer, metabolic, and neurodegenerative pathologies, notably Alzheimer's and Parkinson disease. The findings reported in the last decade are starting to help to decipher the complex relations between plant polyphenols and cell homeostatic systems including metabolic and redox equil., proteostasis, and the inflammatory response, establishing an increasingly solid mol. basis for the healthy effects of these mols. Taken together, the data currently available, though still incomplete, are providing a rationale for the possible use of natural polyphenols, or their mol. scaffolds, as nutraceuticals to contrast aging and to combat many assocd. pathologies.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhslGmt7%252FN&md5=8bfe06c440f984df718a7db0c12e74e0
  25. 25
    Rigacci, S., Guidotti, V., Bucciantini, M., Parri, M., Nediani, C., Cerbai, E., Stefani, M., and Berti, A. (2010) Oleuropein Aglycon Prevents Cytotoxic Amyloid Aggregation of Human Amylin. J. Nutr. Biochem. 21 (8), 726– 735,  DOI: 10.1016/j.jnutbio.2009.04.010
    Google Scholar
    25
    Oleuropein aglycon prevents cytotoxic amyloid aggregation of human amylin
    Rigacci, Stefania; Guidotti, Valentina; Bucciantini, Monica; Parri, Matteo; Nediani, Chiara; Cerbai, Elisabetta; Stefani, Massimo; Berti, Andrea
    Journal of Nutritional Biochemistry (2010), 21 (8), 726-735CODEN: JNBIEL; ISSN:0955-2863. (Elsevier)
    Pancreatic amyloid deposits of amylin are a hallmark of Type II diabetes and considerable evidence indicates that amylin oligomers are cytotoxic to β-cells. Many efforts are presently spent to find out naturally occurring mols., or to design synthetic ones, able to hinder amylin aggregation or to protect cells against aggregate cytotoxicity. In this context, a protective effect of some polyphenols against amyloid cytotoxicity was reported. Actually dietary polyphenols are endowed with multiple health benefits, and extra virgin olive oil is attracting increasing interest as a source of these substances. Here, we investigated the effects on amylin aggregation and cytotoxicity of the secoiridoid oleuropein aglycon, the main phenolic component of extra virgin olive oil. We found that oleuropein, when present during the aggregation of amylin, consistently prevented its cytotoxicity to RIN-5F pancreatic β-cells, as detd. by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide test and caspase-3 activity assay. A lack of interaction with the cell membrane of amylin aggregates grown in the presence of oleuropein was shown by fluorescence microscopy and synthetic lipid vesicle permeabilization. Moreover, our ThT assay, CD anal. and electron microscopy images suggested that oleuropein interferes with amylin aggregation, resulting in a different path skipping the formation of toxic pre-fibrillar aggregates. These results provide a mol. basis for some of the benefits potentially coming from extra virgin olive oil consumption and pave the way to further studies on the possible pharmacol. use of oleuropein to prevent or to slow down the progression of type II diabetes.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXptVamt78%253D&md5=8571339f9624289049a490f0e25d965a
  26. 26
    Leri, M., Nosi, D., Natalello, A., Porcari, R., Ramazzotti, M., Chiti, F., Bellotti, V., Doglia, S. M., Stefani, M., and Bucciantini, M. (2016) The Polyphenol Oleuropein Aglycone Hinders the Growth of Toxic Transthyretin Amyloid Assemblies. J. Nutr. Biochem. 30, 153– 166,  DOI: 10.1016/j.jnutbio.2015.12.009
    Google Scholar
    26
    The polyphenol Oleuropein aglycone hinders the growth of toxic transthyretin amyloid assemblies
    Leri, Manuela; Nosi, Daniele; Natalello, Antonino; Porcari, Riccardo; Ramazzotti, Matteo; Chiti, Fabrizio; Bellotti, Vittorio; Doglia, Silvia Maria; Stefani, Massimo; Bucciantini, Monica
    Journal of Nutritional Biochemistry (2016), 30 (), 153-166CODEN: JNBIEL; ISSN:0955-2863. (Elsevier)
    Transthyretin (TTR) is involved in a subset of familial or sporadic amyloid diseases including senile systemic amyloidosis (SSA), familial amyloid polyneuropathy and cardiomyopathy (FAP/FAC) for which no effective therapy has been found yet. These conditions are characterized by extracellular deposits primarily found in the heart parenchyma and in peripheral nerves whose main component are amyloid fibrils, presently considered the main culprits of cell sufferance. The latter are polymeric assemblies grown from misfolded TTR, either wt or carrying one out of many identified mutations. The recent introduction in the clin. practice of synthetic TTR-stabilizing mols. that reduce protein aggregation provides the rationale to search natural effective mols. able to interfere with TTR amyloid aggregation by hindering the appearance of toxic species or by favoring the growth of harmless aggregates. Here we carried out an in depth biophys. and morphol. study on the mol. features of the aggregation of wt- and L55P-TTR involved in SSA or FAP/FAC, resp., and on the interference with fibril aggregation, stability and toxicity to cardiac HL-1 cells to demonstrate the ability of Oleuropein aglycon (OleA), the main phenolic component of the extra virgin olive oil. We describe the mol. basis of such interference and the resulting redn. of TTR amyloid aggregate cytotoxicity. Our data offer the possibility to validate and optimize the use of OleA or its mol. scaffold to rationally design promising drugs against TTR-related pathologies that could enter a clin. exptl. phase.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xis1Gis7g%253D&md5=df648a9675770f47caa514e982d62264
  27. 27
    Rigacci, S., Guidotti, V., Bucciantini, M., Nichino, D., Relini, A., Berti, A., and Stefani, M. (2011) Aβ(1–42) Aggregates into Non-Toxic Amyloid Assemblies in the Presence of the Natural Polyphenol Oleuropein Aglycon. Curr. Alzheimer Res. 8 (8), 841– 852,  DOI: 10.2174/156720511798192682
    Google Scholar
    27
    Aβ(1-42) aggregates into non-toxic amyloid assemblies in the presence of the natural polyphenol oleuropein aglycon
    Rigacci, Stefania; Guidotti, Valentina; Bucciantini, Monica; Nichino, Daniela; Relini, Annalisa; Berti, Andrea; Stefani, Massimo
    Current Alzheimer Research (2011), 8 (8), 841-852CODEN: CARUBY; ISSN:1567-2050. (Bentham Science Publishers Ltd.)
    Amyloid aggregation starts with the initial misfolding of peptide/protein precursors, with subsequent structural rearrangement into oligomers and protofibrils; the latter eventually organize into fibrils with shared basic structural features, found deposited in amyloid diseases. Mounting evidence indicates early oligomers as the most toxic amyloid species; accordingly, the search of inhibitors of their growth is considered a promising target to prevent amyloid toxicity. We recently showed that oleuropein aglycon, a polyphenol abundant in the extra virgin olive oil, interferes with the aggregation of amylin (involved in type-2 diabetes), eliminating its cytotoxicity. Here we report that oleuropein aglycon also hinders amyloid aggregation of Aβ(1-42) and its cytotoxicity, suggesting a general effect of such polyphenol. In particular, by a wide panel of different spectroscopic, immunol., cell viability and imaging techniques we provide a more detailed description of Aβ(1-42) structural modifications arising in the presence of the inhibitor and the resulting cytotoxicity. We here report that the polyphenol eliminates the appearance of early toxic oligomers favoring the formation of stable harmless protofibrils, structurally different from the typical Aβ(1-42) fibrils. We also show that oleuropein aglycon is maximally effective when is present at the beginning of the aggregation process; furthermore, when added to pre-formed fibrils, it does not induce the release of toxic oligomers but, rather, neutralizes any residual toxicity possibly arising from the residual presence of traces of sol. oligomers and other toxic aggregates. The possible use of this polyphenol as anti-aggregation mol. is discussed in the light of these data.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhs1ShtrvN&md5=4280c13b299c367bc10a8e52145a8ffc
  28. 28
    Palazzi, L., Bruzzone, E., Bisello, G., Leri, M., Stefani, M., Bucciantini, M., and Polverino de Laureto, P. (2018) Oleuropein Aglycone Stabilizes the Monomeric α-Synuclein and Favours the Growth of Non-Toxic Aggregates. Sci. Rep. 8 (1), 8337,  DOI: 10.1038/s41598-018-26645-5
    Google Scholar
    28
    Oleuropein aglycone stabilizes the monomeric α-synuclein and favours the growth of non-toxic aggregates
    Palazzi Luana; Bisello Giovanni; Polverino de Laureto Patrizia; Bruzzone Elena; Leri Manuela; Stefani Massimo; Bucciantini Monica; Leri Manuela
    Scientific reports (2018), 8 (1), 8337 ISSN:.
    α-synuclein plays a key role in the pathogenesis of Parkinson's disease (PD); its deposits are found as amyloid fibrils in Lewy bodies and Lewy neurites, the histopathological hallmarks of PD. Amyloid fibrillation is a progressive polymerization path starting from peptide/protein misfolding and proceeding through the transient growth of oligomeric intermediates widely considered as the most toxic species. Consequently, a promising approach of intervention against PD might be preventing α-synuclein build-up, misfolding and aggregation. A possible strategy involves the use of small molecules able to slow down the aggregation process or to alter oligomer conformation favouring the growth of non-pathogenic species. Here, we show that oleuropein aglycone (OleA), the main olive oil polyphenol, exhibits anti-amyloidogenic power in vitro by interacting with, and stabilizing, α-synuclein monomers thus hampering the growth of on-pathway oligomers and favouring the growth of stable and harmless aggregates with no tendency to evolve into other cytotoxic amyloids. We investigated the molecular basis of such interference by both biophysical techniques and limited proteolysis; aggregate morphology was monitored by electron microscopy. We also found that OleA reduces the cytotoxicity of α-synuclein aggregates by hindering their binding to cell membrane components and preventing the resulting oxidative damage to cells.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MbhsFemtg%253D%253D&md5=e9bed4333ac2bf282a12dc0f4994ee47
  29. 29
    Leri, M., Natalello, A., Bruzzone, E., Stefani, M., and Bucciantini, M. (2019) Oleuropein Aglycone and Hydroxytyrosol Interfere Differently with Toxic Aβ1–42 Aggregation. Food Chem. Toxicol. 129, 1– 12,  DOI: 10.1016/j.fct.2019.04.015
    Google Scholar
    29
    Oleuropein aglycone and hydroxytyrosol interfere differently with toxic Aβ1-42 aggregation
    Leri, Manuela; Natalello, Antonino; Bruzzone, Elena; Stefani, Massimo; Bucciantini, Monica
    Food and Chemical Toxicology (2019), 129 (), 1-12CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)
    Oleuropein aglycon (OleA), the most abundant polyphenol in extra virgin olive oil (EVOO), and Hydroxythyrosol (HT), the OleA main metabolite, have attracted our interest due to their multitarget effects, including the interference with amyloid aggregation path. However, the mechanistic details of their anti-amyloid effect are not known yet. We report here a broad biophys. approach and cell biol. techniques that enabled us to characterize the different mol. mechanisms by which OleA and HT modulate the Aβ1-42 fibrillation, a main histopathol. feature of Alzheimer's disease (AD). In particular, OleA prevents the growth of toxic Aβ1-42 oligomers and blocks their successive growth into mature fibrils following its interaction with the peptide N-terminus, while HT speeds up harmless fibril formation. Our data demonstrate that, by stabilizing oligomers and fibrils, both polyphenols reduce their seeding activity and aggregate/membrane interaction on human neuroblastoma SH-SY5Y cells. These findings highlight the great potential of EVOO polyphenols and offer the possibility to validate and to optimize their use for possible AD prevention and therapy.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXnvF2ht7s%253D&md5=3863c374b1298e87ce4fb3add2a6419f
  30. 30
    Palazzi, L., Leri, M., Cesaro, S., Stefani, M., Bucciantini, M., and Polverino de Laureto, P. (2020) Insight into the Molecular Mechanism Underlying the Inhibition of α-Synuclein Aggregation by Hydroxytyrosol. Biochem. Pharmacol. 173, 113722,  DOI: 10.1016/j.bcp.2019.113722
    Google Scholar
    30
    Insight into the molecular mechanism underlying the inhibition of α-synuclein aggregation by hydroxytyrosol
    Palazzi, Luana; Leri, Manuela; Cesaro, Samuele; Stefani, Massimo; Bucciantini, Monica; Polverino de Laureto, Patrizia
    Biochemical Pharmacology (Amsterdam, Netherlands) (2020), 173 (), 113722CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)
    Parkinson's disease (PD) is the second most prevalent neurodegenerative disease in the elderly people. To date, drugs able to reverse the disease are not available; the gold std. is levodopa that only relieves clin. symptoms, yet with severe side effects after prolonged administration. Many efforts are underway to find alternative targets for PD prevention or treatment, the most promising being α-synuclein (Syn). Recently, we reported that oleuropein aglycon (OleA) interferes with amyloid aggregation of Syn both stabilizing its monomeric state and inducing the formation of harmless, off-pathway oligomers. This study is focused at describing the interaction between Syn and hydroxytyrosol (HT), the phenolic moiety and main metabolite of OleA, and the interferences with Syn aggregation by using biophys. and biol. techniques. Our results show that HT dose-dependently inhibits Syn aggregation and that covalent and non-covalent binding mediate HT-Syn interaction. HT does not modify the natively unfolded structure of Syn, rather, it stabilizes specific regions of the mol. leading to inhibition of protein fibrillation. Cellular assays showed that HT reduces the toxicity of Syn aggregates. Moreover, Syn aggregates interaction with the cell membrane, an important factor for prion-like properties of Syn on-pathway oligomers, was reduced in cells exposed to Syn aggregates grown in the presence of HT.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXit12ktL7F&md5=a4445287929f44b1f225758d549bf706
  31. 31
    Daccache, A., Lion, C., Sibille, N., Gerard, M., Slomianny, C., Lippens, G., and Cotelle, P. (2011) Oleuropein and Derivatives From Olives as Tau Aggregation Inhibitors. Neurochem. Int. 58 (6), 700– 707,  DOI: 10.1016/j.neuint.2011.02.010
    Google Scholar
    31
    Oleuropein and derivatives from olives as Tau aggregation inhibitors
    Daccache, Anthony; Lion, Cedric; Sibille, Nathalie; Gerard, Melanie; Slomianny, Christian; Lippens, Guy; Cotelle, Philippe
    Neurochemistry International (2011), 58 (6), 700-707CODEN: NEUIDS; ISSN:0197-0186. (Elsevier Ltd.)
    Tau isoforms constitute a family of microtubule-assocd. proteins that are mainly expressed in neurons of the central nervous system. They promote the assembly of tubulin monomers into microtubules and modulate their stability, thus playing a key structural role in the distal portion of axons. In Alzheimer's disease and related tauopathies, Tau aggregation into fibrillary tangles contributes to intraneuronal and glial lesions. We report herein the ability of three natural phenolic derivs. obtained from olives and derived food products to prevent such Tau fibrillization in vitro, namely hydroxytyrosol, oleuropein, and oleuropein aglycon. The latter was found to be more active than the ref. Tau aggregation inhibitor methylene blue on both wild-type and P301L Tau proteins, inhibiting fibrillization at low micromolar concns. These findings might provide further exptl. support for the beneficial nutritional properties of olives and olive oil as well as a chem. scaffold for the development of new drugs aiming at neurodegenerative tauopathies.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXksFGmtLw%253D&md5=94c9cf92c95514c8dc8b024f96d53ce2
  32. 32
    Leri, M., Oropesa-Nuñez, R., Canale, C., Raimondi, S., Giorgetti, S., Bruzzone, E., Bellotti, V., Stefani, M., and Bucciantini, M. (2018) Oleuropein Aglycone: A Polyphenol with Different Targets Against Amyloid Toxicity. Biochim. Biophys. Acta, Gen. Subj. 1862 (6), 1432– 1442,  DOI: 10.1016/j.bbagen.2018.03.023
    Google Scholar
    32
    Oleuropein aglycone: A polyphenol with different targets against amyloid toxicity
    Leri, Manuela; Oropesa-Nunez, Reiner; Canale, Claudio; Raimondi, Sara; Giorgetti, Sofia; Bruzzone, Elena; Bellotti, Vittorio; Stefani, Massimo; Bucciantini, Monica
    Biochimica et Biophysica Acta, General Subjects (2018), 1862 (6), 1432-1442CODEN: BBGSB3; ISSN:0304-4165. (Elsevier B.V.)
    Many data highlight the benefits of the Mediterranean diet and its main lipid component, extra-virgin olive oil (EVOO). EVOO contains many phenolic compds. that have been found effective against several aging- and lifestyle-related diseases, including neurodegeneration. Oleuropein, a phenolic secoiroid glycoside, is the main polyphenol in the olive oil. It has been reported that the aglycon form of Oleuropein (OleA) interferes in vitro and in vivo with amyloid aggregation of a no. of proteins/peptides involved in amyloid, particularly neurodegenerative, diseases avoiding the growth of toxic oligomers and displaying protection against cognitive deterioration. In this study, we carried out a cellular and biophys. study on the relationships between the effects of OleA on the aggregation and cell interactions of the D76N β2-microglobulin (D76N b2m) variant assocd. with a familial form of systemic amyloidosis with progressive bowel dysfunction and extensive visceral amyloid deposits. Our results indicate that OleA protection against D76N b2m cytotoxicity results from (i) a modification of the conformational and biophys. properties of its amyloid fibrils; (ii) a modification of the cell bilayer surface properties of exposed cells. This study reveals that OleA remodels not only D76N b2m aggregates but also the cell membrane interfering with the misfolded proteins-cell membrane assocn., in most cases an early event triggering amyloid-mediated cytotoxicity. The data provided in the present article focus on OleA protection, featuring this polyphenol as a promising plant mol. useful against amyloid diseases.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXmsVKitL4%253D&md5=e3762313d1252ea3bf5f2cd7a8361f18
  33. 33
    Rigacci, S., Miceli, C., Nediani, C., Berti, A., Cascella, R., Pantano, D., Nardiello, P., Luccarini, I., Casamenti, F., and Stefani, M. (2015) Oleuropein Aglycone Induces Autophagy via the AMPK/mTOR Signalling Pathway: A Mechanistic Insight. Oncotarget 6 (34), 35344– 35357,  DOI: 10.18632/oncotarget.6119
    Google Scholar
    33
    Oleuropein aglycone induces autophagy via the AMPK/mTOR signalling pathway: a mechanistic insight
    Rigacci Stefania; Miceli Caterina; Nediani Chiara; Berti Andrea; Cascella Roberta; Stefani Massimo; Pantano Daniela; Nardiello Pamela; Luccarini Ilaria; Casamenti Fiorella
    Oncotarget (2015), 6 (34), 35344-57 ISSN:.
    The healthy effects of plant polyphenols, some of which characterize the so-called Mediterranean diet, have been shown to arise from epigenetic and biological modifications resulting, among others, in autophagy stimulation. Our previous work highlighted the beneficial effects of oleuropein aglycone (OLE), the main polyphenol found in the extra virgin olive oil, against neurodegeneration both in cultured cells and in model organisms, focusing, in particular, autophagy activation. In this study we investigated more in depth the molecular and cellular mechanisms of autophagy induction by OLE using cultured neuroblastoma cells and an OLE-fed mouse model of amylod beta (Aβ) deposition. We found that OLE triggers autophagy in cultured cells through the Ca2+-CAMKKβ-AMPK axis. In particular, in these cells OLE induces a rapid release of Ca2+ from the SR stores which, in turn, activates CAMKKβ, with subsequent phosphorylation and activation of AMPK. The link between AMPK activation and mTOR inhibition was shown in the OLE-fed animal model in which we found that decreased phospho-mTOR immunoreactivity and phosphorylated mTOR substrate p70 S6K levels match enhanced phospho-AMPK levels, supporting the idea that autophagy activation by OLE proceeds through mTOR inhibition. Our results agree with those reported for other plant polyphenols, suggesting a shared molecular mechanism underlying the healthy effects of these substances against ageing, neurodegeneration, cancer, diabetes and other diseases implying autophagy dysfunction.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28zitlGmuw%253D%253D&md5=4ed55c7e2bd9c10917d22d132d6a7752
  34. 34
    Grossi, C., Rigacci, S., Ambrosini, S., Ed Dami, T., Luccarini, I., Traini, C., Failli, P., Berti, A., Casamenti, F., and Stefani, M. (2013) The Polyphenol Oleuropein Aglycone Protects TgCRND8Mice against Aß Plaque Pathology. PLoS One 8 (8), e71702  DOI: 10.1371/journal.pone.0071702
    Google Scholar
    34
    The polyphenol oleuropein aglycone protects TgCRND8 mice against Aβ plaque pathology
    Grossi, Cristina; Rigacci, Stefania; Ambrosini, Stefano; Ed Dami, Teresa; Luccarini, Ilaria; Traini, Chiara; Failli, Paola; Berti, Andrea; Casamenti, Fiorella; Stefani, Massimo
    PLoS One (2013), 8 (8), e71702CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
    The claimed beneficial effects of the Mediterranean diet include prevention of several age-related dysfunctions including neurodegenerative diseases and Alzheimer-like pathol. These effects have been related to the protection against cognitive decline assocd. with aging and disease by a no. of polyphenols found in red wine and extra virgin olive oil. The double transgenic TgCRND8 mice (overexpressing the Swedish and Indiana mutations in the human amyloid precursor protein), aged 1.5 and 4, and age-matched wild type control mice were used to examine in vivo the effects of 8 wk dietary supplementation of oleuropein aglycon (50 mg/kg of diet), the main polyphenol found in extra virgin olive oil. We report here that dietary supplementation of oleuropein aglycon strongly improves the cognitive performance of young/middle-aged TgCRND8 mice, a model of amyloid-β deposition, respect to age-matched littermates with un-supplemented diet. Immunofluorescence anal. of cerebral tissue in oleuropein aglycon-fed transgenic mice showed remarkably reduced β-amyloid levels and plaque deposits, which appeared less compact and "fluffy"; moreover, microglia migration to the plaques for phagocytosis and a remarkable redn. of the astrocyte reaction were evident. Finally, oleuropein aglycon-fed mice brain displayed an astonishingly intense autophagic reaction, as shown by the increase of autophagic markers expression and of lysosomal activity. Data obtained with cultured cells confirmed the latter evidence, suggesting mTOR regulation by oleuropein aglycon. Our results support, and provide mechanistic insights into, the beneficial effects against Alzheimer-assocd. neurodegeneration of a polyphenol enriched in the extra virgin olive oil, a major component of the Mediterranean diet.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtlamsrfI&md5=0cabef823648e2452389ed35a0320d17
  35. 35
    Luccarini, I., Pantano, D., Nardiello, P., Cavone, L., Lapucci, A., Miceli, C., Nediani, C., Berti, A., Stefani, M., and Casamenti, F. (2016) The Polyphenol Oleuropein Aglycone Modulates the PARP1-SIRT1 Interplay: An In Vitro and In Vivo Study. J. Alzheimer's Dis. 54 (2), 737– 750,  DOI: 10.3233/JAD-160471
    Google Scholar
    35
    The Polyphenol Oleuropein Aglycone Modulates the PARP1-SIRT1 Interplay: An In Vitro and In Vivo Study
    Luccarini, Ilaria; Pantano, Daniela; Nardiello, Pamela; Cavone, Leonardo; Lapucci, Andrea; Miceli, Caterina; Nediani, Chiara; Berti, Andrea; Stefani, Massimo; Casamenti, Fiorella; Cassano, Tommaso
    Journal of Alzheimer's Disease (2016), 54 (2), 737-750CODEN: JADIF9; ISSN:1387-2877. (IOS Press)
    Poly(ADP-ribose) polymerase-1 (PARP1) activation contributes to the cascade of events initiated by amyloid-β (Aβ) peptide eventually leading to cell death in Alzheimer's disease brain. A significant accumulation of PAR polymers and increase of PARP1 expression were detected in the cortex at the early (3.5 mo) and intermediate (6 mo) stage of Aβ deposition in the TgCRND8 mouse model. Our previous data highlighted the beneficial effects of oleuropein aglycon (OLE), the main polyphenol found in the olive oil, against neurodegeneration both in cultured cells and in model organisms. Here we found that 8-wk OLE treatment (50mg/kg of diet) to 6-mo-old TgCRND8 mice rescued to control values PARP1 activation and the levels of its product, PAR. In N2a neuroblastoma cells, PARP1 activation and PAR formation upon exposure to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were abolished by pretreatment for 24h with either OLE (100μM) or PARP inhibitors. A significant redn. of the NAD+ content, compared to controls, was found in N2a cells exposed to MNNG (100μM) for 90min; the latter was slightly attenuated by cell treatment for 24h with PJ-34 or with OLE. In vitro and in vivo, the OLE-induced redn. of PARP1 activation was paralleled by the overexpression of Sirtuin1 (SIRT1), and, in vivo, by a decrease of NF-κB and the pro-apoptotic marker p53. In N2a cells, we also found that OLE potentiates the MNNG-induced increase of Beclin1 levels. In conclusion, our data show that OLE treatment counteracts neuronal damage through modulation of the PARP1-SIRT1 interplay.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVyisrrN&md5=41ee6b88a89ab8643d3fa9cf6f5a723f
  36. 36
    LeVine, H. (1995) Thioflavine T Interaction with Amyloid β-sheet Structures. Amyloid 2 (1), 1– 6,  DOI: 10.3109/13506129509031881
    Google Scholar
    36
    Thioflavine T interaction with amyloid β-sheet structures
    LeVine, Harry III
    Amyloid (1995), 2 (1), 1-6CODEN: AIJIET; ISSN:1350-6129.
    Thioflavine T (ThT) interacts in tissue sections with amyloid deposits comprised of a variety of protein species giving a characteristic fluorescent complex. Binding of the dye to amyloid fibrils in suspension generates an amyloid-specific fluorescent signal. This interaction with amyloid fibrils formed from different polypeptides and proteins contg. antiparallel β-pleated sheet secondary structure is selective, occurring strongly with amyloid fibrils formed from insulin, transthyretin, polyglycine(I), Aβ(1-40), and weakly with β2-microglobulin. No fluorescence changes were seen with β-sheet fibrillar poly-L-lysine, islet amyloid peptide (20-29), or poly-L-serine. Native forms of transthyretin, insulin, β2-microglobulin, poly-L-lysine, Aβ(1-40), or several proteins contg. high percentages of β-sheet were also unreactive. The affinity of the amyloid fibrils for ThT varied: (apparent Kd's 0.033 - 10 μM; Amyloid A protein < insulin < ApoAII < polyglycine < transthyretin < Aβ(1-40)). The spectral changes induced by the different amyloid fibrils are qual. the same regardless of the pKd of the interaction with ThT or the identity of the amyloid fibrils, suggesting that the quaternary and secondary, but not the primary structure of the amyloid fibrils are important in forming the amyloid fibril-specific ThT species. Thus, Thioflavine T provides a useful tool for the investigation of amyloidogenesis in a variety of systems.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXlsFyhs7g%253D&md5=4e7b589b31c163fd215a025a16664d49
  37. 37
    Pansieri, J., Ostojić, L., Iashchishyn, I. A., Magzoub, M., Wallin, C., Wärmländer, S. K. T. S., Gräslund, A., Nguyen Ngoc, M., Smirnovas, V., Svedružić, Ž. (2019) Pro-Inflammatory S100A9 Protein Aggregation Promoted by NCAM1 Peptide Constructs. ACS Chem. Biol. 14 (7), 1410– 1417,  DOI: 10.1021/acschembio.9b00394
    Google Scholar
    37
    Pro-inflammatory S100A9 protein aggregation promoted by NCAM1 peptide constructs
    Pansieri, Jonathan; Ostojic, Lucija; Iashchishyn, Igor A.; Magzoub, Mazin; Wallin, Cecilia; Waermlaender, Sebastian K. T. S.; Graeslund, Astrid; Nguyen Ngoc, Mai; Smirnovas, Vytautas; Svedruzic, Zeljko; Morozova-Roche, Ludmilla A.
    ACS Chemical Biology (2019), 14 (7), 1410-1417CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
    Amyloid cascade and neuroinflammation are hallmarks of neurodegenerative diseases, and pro-inflammatory S100A9 protein is central to both of them. Here, we have shown that NCAM1 peptide constructs carrying polycationic sequences derived from Aβ peptide (KKLVFF) and PrP protein (KKRPKP) significantly promote the S100A9 amyloid self-assembly in a concn.-dependent manner by making transient interactions with individual S100A9 mols., perturbing its native structure and acting as catalysts. Since the individual mol. misfolding is a rate-limiting step in S100A9 amyloid aggregation, the effects of the NCAM1 construct on the native S100A9 are so crit. for its amyloid self-assembly. S100A9 rapid self-assembly into large aggregated clumps may prevent its amyloid tissue propagation, and by modulating S100A9 aggregation as a part of the amyloid cascade, the whole process may be effectively tuned.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtV2lsLjM&md5=994b31d58e7e135544a71406e5148697
  38. 38
    Ferrone, F. (1999) Analysis of Protein Aggregation Kinetics. In Amyloid, Prions, and Other Protein Aggregates, Methods in Enzymology, Vol. 309, pp 256– 274, Academic Press, New York. DOI: 10.1016/S0076-6879(99)09019-9 .
    Google Scholar
    There is no corresponding record for this reference.
  39. 39
    Pansieri, J., Iashchishyn, I. A., Fakhouri, H., Ostojić, L., Malisauskas, M., Musteikyte, G., Smirnovas, V., Schneider, M. M., Scheidt, T., Xu, C. K. (2020) Templating S100A9 Amyloids on Aβ Fibrillar Surfaces Revealed by Charge Detection Mass Spectrometry, Microscopy, Kinetic and Microfluidic Analyses. Chem. Sci. 11 (27), 7031– 7039,  DOI: 10.1039/C9SC05905A
    Google Scholar
    39
    Templating S100A9 amyloids on Aβ fibrillar surfaces revealed by charge detection mass spectrometry, microscopy, kinetic and microfluidic analyses
    Pansieri, Jonathan; Iashchishyn, Igor A.; Fakhouri, Hussein; Ostojic, Lucija; Malisauskas, Mantas; Musteikyte, Greta; Smirnovas, Vytautas; Schneider, Matthias M.; Scheidt, Tom; Xu, Catherine K.; Meisl, Georg; Knowles, Tuomas P. J.; Gazit, Ehud; Antoine, Rodolphe; Morozova-Roche, Ludmilla A.
    Chemical Science (2020), 11 (27), 7031-7039CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
    The mechanism of amyloid co-aggregation and its nucleation process are not fully understood in spite of extensive studies. Deciphering the interactions between proinflammatory S100A9 protein and Aβ42 peptide in Alzheimer's disease is fundamental since inflammation plays a central role in the disease onset. Here we use innovative charge detection mass spectrometry (CDMS) together with biophys. techniques to provide mechanistic insight into the co-aggregation process and differentiate amyloid complexes at a single particle level. Combination of mass and charge distributions of amyloids together with reconstruction of the differences between them and detailed microscopy reveals that co-aggregation involves templating of S100A9 fibrils on the surface of Aβ42 amyloids. Kinetic anal. further corroborates that the surfaces available for the Aβ42 secondary nucleation are diminished due to the coating by S100A9 amyloids, while the binding of S100A9 to Aβ42 fibrils is validated by a microfluidic assay. We demonstrate that synergy between CDMS, microscopy, kinetic and microfluidic analyses opens new directions in interdisciplinary research.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtFOqtrjM&md5=870909e223e6273b417714be73311647
  40. 40
    Lambert de Malezieu, M., Ferron, S., Sauvager, A., Courtel, P., Ramassamy, C., Tomasi, S., and Abasq, M.-L. (2019) UV-Vis Spectroelectrochemistry of Oleuropein, Tyrosol, and p-Coumaric Acid Individually and in an Equimolar Combination. Differences in LC-ESI-MS2 Profiles of Oxidation Products and Their Neuroprotective Properties. Biomolecules 9 (12), 802,  DOI: 10.3390/biom9120802
    Google Scholar
    40
    UV-vis spectroelectrochemistry of oleuropein, tyrosol, and p-coumaric acid individually and in an equimolar combination. Differences in LC-ESI-MS2 profiles of oxidation products and their neuroprotective properties
    Lambert de Malezieu, Morgane; Ferron, Solenn; Sauvager, Aurelie; Courtel, Patricia; Ramassamy, Charles; Tomasi, Sophie; Abasq, Marie-Laurence
    Biomolecules (2019), 9 (12), 802CODEN: BIOMHC; ISSN:2218-273X. (MDPI AG)
    Major phenolic compds. from olive oil (ArOH-EVOO), oleuropein (Ole), tyrosol (Tyr), and p-coumaric acid (p-Cou), are known for their antioxidant and neuroprotective properties. We previously demonstrated that their combination could potentiate their antioxidant activity in vitro and in cellulo. To further our knowledge of their electron-transfer properties, Ole, Tyr, and p-Cou underwent a spectroelectrochem. study, performed either individually or in equimolar mixts. Two mixts. (Mix and Mix-seq) were prepd. in order to det. whether distinct mols. could arise from their simultaneous or sequential oxidn. The comparison of Liq. Chromatog.-Electrospray Ionization-Tandem Mass Spectrometry (LC-ESI-MS2) profiles highlighted the presence of specific oxidized products found in the mixes. We hypothesized that they derived from the dimerization between Tyr and Ole or p-Cou, which have reacted either in their native or oxidized forms. Moreover, Ole regenerates when the Mix undergoes oxidn. Our study also showed significant neuroprotection by oxidized Ole and oxidized Mix against H2O2 toxicity on SK-N-SH cells, after 24 h of treatment with very low concns. (1 and 5 nM). This suggests the putative relevant role of oxidized Ole products to protect or delay neuronal death.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisVOisbzF&md5=bce247f0495156061750c7fcec67e4e5
  41. 41
    Chang, C. C., Khan, I., Tsai, K. L., Li, H., Yang, L. W., Chou, R. H., and Yu, C. (2016) Blocking the Interaction between S100A9 and RAGE V Domain using CHAPS Molecule: A novel route to Drug Development Against Cell Proliferation. Biochim. Biophys. Acta, Proteins Proteomics 1864 (11), 1558– 69,  DOI: 10.1016/j.bbapap.2016.08.008
    Google Scholar
    41
    Blocking the interaction between S100A9 and RAGE V domain using CHAPS molecule: A novel route to drug development against cell proliferation
    Chang, Chin-Chi; Khan, Imran; Tsai, Kun-Lin; Li, Hongchun; Yang, Lee-Wei; Chou, Ruey-Hwang; Yu, Chin
    Biochimica et Biophysica Acta, Proteins and Proteomics (2016), 1864 (11), 1558-1569CODEN: BBAPBW; ISSN:1570-9639. (Elsevier B.V.)
    Human S100A9 (Calgranulin B) is a Ca2+-binding protein, from the S100 family, that often presents as a homodimer in myeloid cells. It becomes an important mediator during inflammation once calcium binds to its EF-hand motifs. Human RAGE protein (receptor for advanced glycation end products) is one of the target-proteins. RAGE binds to a hydrophobic surface on S100A9. Interactions between these proteins trigger signal transduction cascades, promoting cell growth, proliferation, and tumorigenesis. Here, we present the soln. structure of mutant S100A9 (C3S) homodimer, detd. by multi-dimensional NMR expts. We further characterize the soln. interactions between mS100A9 and the RAGE V domain via NMR spectroscopy. CHAPS is a zwitterionic and non-denaturing mol. widely used for protein solubilizing and stabilization. We found out that CHAPS and RAGE V domain would interact with mS100A9 by using 1H-15N HSQC NMR titrns. Therefore, using the HADDOCK program, we superimpose two binary complex models mS100A9-RAGE V domain and mS100A9-CHAPS and demonstrate that CHAPS mols. could play a crucial role in blocking the interaction between mS100A9 and the RAGE V domain. WST-1 assay results also support the conclusion that CHAPS inhibits the bioactivity of mS100A9. This report will help to inform new drug development against cell proliferation.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtleitrrJ&md5=edf7f6363b5d98376e5294ef68a8fe16
  42. 42
    Ferrer, I., Blanco, R., Carmona, M., Puig, B., Ribera, R., Rey, M. J., and Ribalta, T. (2001) Prion Protein Expression in Senile Plaques in Alzheimer’s Disease. Acta Neuropathol. 101 (1), 49– 56,  DOI: 10.1007/s004010000271
    Google Scholar
    42
    Prion protein expression in senile plaques in Alzheimer's disease
    Ferrer, I.; Blanco, R.; Carmona, M.; Puig, B.; Ribera, R.; Rey, M. J.; Ribalta, T.
    Acta Neuropathologica (2001), 101 (1), 49-56CODEN: ANPTAL; ISSN:0001-6322. (Springer-Verlag)
    Prion protein (PrPC) is a glycolipid-anchored cell membrane sialoglycoprotein that localizes in presynaptic membranes. Since synapses are vulnerable to Alzheimer's disease (AD), the present study examines PrPC expression in senile plaques, one of the major structural abnormalities in AD, by single- and double-labeling immunohistochem. Punctate PrPC immunoreactivity is found in diffuse plaques, whereas isolated large coarse PrPC-pos. granules reminiscent of dystrophic neurites are obsd. in neuritic plaques. Finally, PrPC deposition also occurs as dense filamentous and amorphous ppts. in amyloid cores of senile plaques, but not in the walls of blood vessels with amyloid angiopathy. In contrast to PrPC, βA4-amyloid immunoreactivity is preserved and even enhanced following incubation of the tissue sections with proteinase K prior to immunohistochem., thus indicating no PrPC and βA4-amyloid cross-reactivity in dense amyloid cores of senile plaques. Punctate PrPC deposition in diffuse plaques is similar to that of synaptophysin, a synaptic vesicle-assocd. protein, as already reported in other studies. Immunopptn., electrophoresis and Western blot studies have shown that synaptophysin, amyloid precursor protein (APP) and βA4 do not co-ppt. with PrP. These results suggest that synaptophysin, APP and βA4 are likely not bound to PrP. PrPC accumulation in βA4-amyloid dense cores may be the consequence of the release of PrP into the extracellular space. Whether PrPC accumulation in the extracellular space is the result of impaired endocytosis and subsequent hydrolysis in the endosomal compartment, in contrast to normal degrdn. of PrPC, resulting from or occurring in parallel to abnormal APP degrdn., deserves further study.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXhtValurs%253D&md5=ad313fb97a3424f0f9f87f3af05b2e20
  43. 43
    Vogl, T., Eisenblätter, M., Völler, T., Zenker, S., Hermann, S., van Lent, P., Faust, A., Geyer, C., Petersen, B., Roebrock, K. (2014) Alarmin S100A8/S100A9 as a Biomarker for Molecular Imaging of Local Inflammatory Activity. Nat. Commun. 5 (1), 4593,  DOI: 10.1038/ncomms5593
    Google Scholar
    43
    Alarmin S100A8/S100A9 as a biomarker for molecular imaging of local inflammatory activity
    Vogl, Thomas; Eisenblaetter, Michel; Voeller, Tom; Zenker, Stefanie; Hermann, Sven; van Lent, Peter; Faust, Andreas; Geyer, Christiane; Petersen, Beatrix; Roebrock, Kirsten; Schaefers, Michael; Bremer, Christoph; Roth, Johannes
    Nature Communications (2014), 5 (), 4593CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)
    Inflammation has a key role in the pathogenesis of various human diseases. The early detection, localization and monitoring of inflammation are crucial for tailoring individual therapies. However, reliable biomarkers to detect local inflammatory activities and to predict disease outcome are still missing. Alarmins, which are locally released during cellular stress, are early amplifiers of inflammation. Here, using optical mol. imaging, we demonstrate that the alarmin S100A8/S100A9 serves as a sensitive local and systemic marker for the detection of even sub-clin. disease activity in inflammatory and immunol. processes like irritative and allergic contact dermatitis. In a model of collagen-induced arthritis, we use S100A8/S100A9 imaging to predict the development of disease activity. Furthermore, S100A8/S100A9 can act as a very early and sensitive biomarker in exptl. leishmaniasis for phagocyte activation linked to an effective Th1-response. In conclusion, the alarmin S100A8/S100A9 is a valuable and sensitive mol. target for novel imaging approaches to monitor clin. relevant inflammatory disorders on a mol. level.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitVaksLfN&md5=12a921b769ee55ecc080d53474332119
  44. 44
    Bucciantini, M., Calloni, G., Chiti, F., Formigli, L., Nosi, D., Dobson, C. M., and Stefani, M. (2004) Prefibrillar Amyloid Protein Aggregates Share Common Features of Cytotoxicity. J. Biol. Chem. 279 (30), 31374– 31382,  DOI: 10.1074/jbc.M400348200
    Google Scholar
    44
    Prefibrillar Amyloid Protein Aggregates Share Common Features of Cytotoxicity
    Bucciantini, Monica; Calloni, Giulia; Chiti, Fabrizio; Formigli, Lucia; Nosi, Daniele; Dobson, Christopher M.; Stefani, Massimo
    Journal of Biological Chemistry (2004), 279 (30), 31374-31382CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
    The intracellular free Ca2+ concn. and redox status of murine fibroblasts exposed to prefibrillar aggregates of the HypF N-terminal domain have been investigated in vitro and in vivo using a range of fluorescent probes. Aggregate entrance into the cytoplasm is followed by an early rise of reactive oxygen species and free Ca2+ levels and eventually by cell death. Such changes correlate directly with the viability of the cells and are not obsd. when cell are cultured in the presence of reducing agents or in Ca2+-free media. In addn., moderate cell stress following exposure to the aggregates was found to be fully reversible. The results show that the cytotoxicity of prefibrillar aggregates of HypF-N, a protein not assocd. with clin. disease, has the same fundamental origin as that produced by similar types of aggregates of proteins linked with specific amyloidoses. These findings suggest that misfolded proteinaceous aggregates stimulate generic cellular responses as a result of the exposure of regions of the structure (such as hydrophobic residues and the polypeptide main chain) that are buried in the normally folded proteins. They also support the idea that a higher no. of degenerative pathologies than previously known might be considered as protein deposition diseases.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXlslOrs7g%253D&md5=f0ab3f11b00cc2b8b23acb99069545e6
  45. 45
    Novitskaya, V., Bocharova, O. V., Bronstein, I., and Baskakov, I. V. (2006) Amyloid Fibrils of Mammalian Prion Protein Are Highly Toxic to Cultured Cells and Primary Neurons. J. Biol. Chem. 281 (19), 13828– 13836,  DOI: 10.1074/jbc.M511174200
    Google Scholar
    45
    Amyloid Fibrils of Mammalian Prion Protein Are Highly Toxic to Cultured Cells and Primary Neurons
    Novitskaya, Vera; Bocharova, Olga V.; Bronstein, Igor; Baskakov, Ilia V.
    Journal of Biological Chemistry (2006), 281 (19), 13828-13836CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
    A growing body of evidence indicates that small, sol. oligomeric species generated from a variety of proteins and peptides rather than mature amyloid fibrils are inherently highly cytotoxic. Here, we show for the first time that mature amyloid fibrils produced from full-length recombinant mammalian prion protein (rPrP) were highly toxic to cultured cells and primary hippocampal and cerebellar neurons. Fibrils induced apoptotic cell death in a time- and dose-dependent manner. The toxic effect of fibrils was comparable with that exhibited by sol. small β-oligomers generated from the same protein. Fibrils prepd. from insulin were not toxic, suggesting that the toxic effect was not solely due to the highly polymeric nature of the fibrillar form. The cell death caused by rPrP fibrils or β-oligomers was substantially reduced when expression of endogenous PrPC was down-regulated by small interfering RNAs. In opposition to the β-oligomer and amyloid fibrils of rPrP, the monomeric α-helical form of rPrP stimulated neurite out-growth and survival of neurons. These studies illustrated that both sol. β-oligomer and amyloid fibrils of the prion protein are intrinsically toxic and confirmed that endogenously expressed PrPC is required for mediating the toxicity of abnormally folded external PrP aggregates.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xkt1ymurY%253D&md5=7dd9e8722bc1997f4d260444248ddd58
  46. 46
    Canale, C., Oropesa-Nuñez, R., Diaspro, A., and Dante, S. (2018) Amyloid and Membrane Complexity: The Toxic Interplay Revealed by AFM. Semin. Cell Dev. Biol. 73, 82– 94,  DOI: 10.1016/j.semcdb.2017.08.046
    Google Scholar
    46
    Amyloid and membrane complexity: The toxic interplay revealed by AFM
    Canale, Claudio; Oropesa-Nunez, Reinier; Diaspro, Alberto; Dante, Silvia
    Seminars in Cell & Developmental Biology (2018), 73 (), 82-94CODEN: SCDBFX; ISSN:1084-9521. (Elsevier Ltd.)
    A review. Lipid membranes play a fundamental role in the pathol. development of protein misfolding diseases. Several pieces of evidence suggest that the lipid membrane could act as a catalytic surface for protein aggregation. Furthermore, a leading theory indicates the interaction between the cell membrane and misfolded oligomer species as the responsible for cytotoxicity, hence, for neurodegeneration in disorders such as Alzheimer's and Parkinson's disease. The definition of the mechanisms that drive the interaction between pathol. protein aggregates and plasma membrane is fundamental for the development of effective therapies for a large class of diseases. Atomic force microscopy (AFM) has been employed to study how amyloid aggregates affect the cell physiol. properties. Considerable efforts were spent to characterize the interaction with model systems, i.e., planar supported lipid bilayers, but some works also addressed the problem directly on living cells. Here, an overview of the main works involving the use of the AFM on both model system and living cells will be provided. Different kind of approaches will be presented, as well as the main results derived from the AFM anal.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFSmsL3J&md5=912b964f5577766e290127a998df02e5
  47. 47
    Walsh, P., Vanderlee, G., Yau, J., Campeau, J., Sim, V. L., Yip, C. M., and Sharpe, S. (2014) The Mechanism of Membrane Disruption by Cytotoxic Amyloid Oligomers Formed by Prion Protein (106–126) is Dependent on Bilayer Composition. J. Biol. Chem. 289 (15), 10419– 10430,  DOI: 10.1074/jbc.M113.515866
    Google Scholar
    47
    The Mechanism of Membrane Disruption by Cytotoxic Amyloid Oligomers Formed by Prion Protein(106-126) Is Dependent on Bilayer Composition
    Walsh, Patrick; Vanderlee, Gillian; Yau, Jason; Campeau, Jody; Sim, Valerie L.; Yip, Christopher M.; Sharpe, Simon
    Journal of Biological Chemistry (2014), 289 (15), 10419-10430CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
    The formation of fibrillar aggregates has long been assocd. with neurodegenerative disorders such as Alzheimer and Parkinson diseases. Although fibrils are still considered important to the pathol. of these disorders, it is now widely understood that smaller amyloid oligomers are the toxic entities along the misfolding pathway. One characteristic shared by the majority of amyloid oligomers is the ability to disrupt membranes, a commonality proposed to be responsible for their toxicity, although the mechanisms linking this to cell death are poorly understood. Here, we describe the phys. basis for the cytotoxicity of oligomers formed by the prion protein (PrP)-derived amyloid peptide PrP(106-126). We show that oligomers of this peptide kill several mammalian cells lines, as well as mouse cerebellar organotypic cultures, and we also show that they exhibit antimicrobial activity. Phys. perturbation of model membranes mimicking bacterial or mammalian cells was investigated using at. force microscopy, polarized total internal reflection fluorescence microscopy, and NMR spectroscopy. Disruption of anionic membranes proceeds through a carpet or detergent model as proposed for other antimicrobial peptides. By contrast, when added to zwitterionic membranes contg. cholesterol-rich ordered domains, PrP(106-126) oligomers induce a loss of domain sepn. and decreased membrane disorder. Loss of raft-like domains may lead to activation of apoptotic pathways, resulting in cell death. This work sheds new light on the phys. mechanisms of amyloid cytotoxicity and is the first to clearly show membrane type-specific modes of action for a cytotoxic peptide.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXmtlCnsbo%253D&md5=6e3cdf9ca126d6309eff637155f6ada0
  48. 48
    Leri, M., Bemporad, F., Oropesa-Nuñez, R., Canale, C., Calamai, M., Nosi, D., Ramazzotti, M., Giorgetti, S., Pavone, F. S., Bellotti, V. (2016) Molecular Insights into Cell Toxicity of a Novel Familial Amyloidogenic Variant of β2-microglobulin. J. Cell. Mol. Med. 20 (8), 1443– 1456,  DOI: 10.1111/jcmm.12833
    Google Scholar
    48
    Molecular insights into cell toxicity of a novel familial amyloidogenic variant of β2-microglobulin
    Leri, Manuela; Bemporad, Francesco; Oropesa-Nunez, Reinier; Canale, Claudio; Calamai, Martino; Nosi, Daniele; Ramazzotti, Matteo; Giorgetti, Sofia; Pavone, Francesco S.; Bellotti, Vittorio; Stefani, Massimo; Bucciantini, Monica
    Journal of Cellular and Molecular Medicine (2016), 20 (8), 1443-1456CODEN: JCMMC9; ISSN:1582-4934. (Wiley-Blackwell)
    The first genetic variant of β2-microglobulin (b2M) assocd. with a familial form of systemic amyloidosis has been recently described. The mutated protein, carrying a substitution of Asp at position 76 with an Asn (D76N b2M), exhibits a strongly enhanced amyloidogenic tendency to aggregate with respect to the wild-type protein. In this study, we characterized the D76N b2M aggregation path and performed an unprecedented anal. of the biochem. mechanisms underlying aggregate cytotoxicity. We showed that, contrarily to what expected from other amyloid studies, early aggregates of the mutant are not the most toxic species, despite their higher surface hydrophobicity. By modulating ganglioside GM1 content in cell membrane or synthetic lipid bilayers, we confirmed the pivotal role of this lipid as aggregate recruiter favoring their cytotoxicity. We finally obsd. that the aggregates bind to the cell membrane inducing an alteration of its elasticity (with possible functional unbalance and cytotoxicity) in GM1-enriched domains only, thus establishing a link between aggregate-membrane contact and cell damage.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1SmtL%252FI&md5=569e255a9a3564a7f0a53904b708a902
  49. 49
    Cicerale, S., Conlan, X. A., Sinclair, A. J., and Keast, R. S. J. (2008) Chemistry and Health of Olive Oil Phenolics. Crit. Rev. Food Sci. Nutr. 49 (3), 218– 236,  DOI: 10.1080/10408390701856223
    Google Scholar
    There is no corresponding record for this reference.
  50. 50
    Bucciantini, M., Nosi, D., Forzan, M., Russo, E., Calamai, M., Pieri, L., Formigli, L., Quercioli, F., Soria, S., Pavone, F. (2012) Toxic Effects of Amyloid Fibrils on Cell Membranes: The Importance of Ganglioside GM1. FASEB J. 26 (2), 818– 831,  DOI: 10.1096/fj.11-189381
    Google Scholar
    50
    Toxic effects of amyloid fibrils on cell membranes: the importance of ganglioside GM1
    Bucciantini, Monica; Nosi, Daniele; Forzan, Mario; Russo, Edda; Calamai, Martino; Pieri, Laura; Formigli, Lucia; Quercioli, Franco; Soria, Silvia; Pavone, Francesco; Savistchenko, Jimmy; Melki, Ronald; Stefani, Massimo
    FASEB Journal (2012), 26 (2), 818-831, 10.1096/fj.11-189381CODEN: FAJOEC; ISSN:0892-6638. (Federation of American Societies for Experimental Biology)
    The interaction of amyloid aggregates with the cell plasma membrane is currently considered among the basic mechanisms of neuronal dysfunction in amyloid neurodegeneration. We used amyloid oligomers and fibrils grown from the yeast prion Sup35p, responsible for the specific prion trait [PSI+], to investigate how membrane lipids modulate fibril interaction with the membranes of cultured H-END cells and cytotoxicity. Sup35p shares no homol. with endogenous mammalian polypeptide chains. Thus, the generic toxicity of amyloids and the mol. events underlying cell degeneration can be investigated without interference with analogous polypeptides encoded by the cell genome. Sup35 fibrils bound to the cell membrane without increasing its permeability to Ca2+. Fibril binding resulted in structural reorganization and aggregation of membrane rafts, with GM1 clustering and alteration of its mobility. Sup35 fibril binding was affected by GM1 or its sialic acid moiety, but not by cholesterol membrane content, with complete inhibition after treatment with fumonisin B1 or neuraminidase. Finally, cell impairment resulted from caspase-8 activation after Fas receptor translocation on fibril binding to the plasma membrane. Our observations suggest that amyloid fibrils induce abnormal accumulation and overstabilization of raft domains in the cell membrane and provide a reasonable, although not unique, mechanistic and mol. explanation for fibril toxicity.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XitFOnt7o%253D&md5=3e235091b37469527df80656e9941281
  51. 51
    Calamai, M. and Pavone, F. S. (2013) Partitioning and Confinement of GM1 Ganglioside induced by Amyloid Aggregates. FEBS Lett. 587 (9), 1385– 1391,  DOI: 10.1016/j.febslet.2013.03.014
    Google Scholar
    51
    Partitioning and confinement of GM1 ganglioside induced by amyloid aggregates
    Calamai, Martino; Pavone, Francesco S.
    FEBS Letters (2013), 587 (9), 1385-1391CODEN: FEBLAL; ISSN:0014-5793. (Elsevier B.V.)
    Growing evidence shows that GM1 ganglioside is involved in amyloid deposition and toxicity. By means of real-time single particle tracking, we show that amyloid oligomers and aggregates formed by Aβ1-42 and amylin, two peptides assocd., resp., with the development of Alzheimer's disease and type II diabetes, interact with GM1 and decrease dramatically its lateral diffusion on the plasma membrane of living neuroblastoma cells. The confinement of GM1, a constituent of membrane rafts involved in neuroprotection, at the level of both types of amyloid aggregates can interfere with cell signaling pathways and contribute to the loss of neuroprotection.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXltFCktL0%253D&md5=8a6120f6badbd0c18f63fd5ec3a1a42e
  52. 52
    Pellistri, F., Bucciantini, M., Relini, A., Nosi, D., Gliozzi, A., Robello, M., and Stefani, M. (2008) Nonspecific Interaction of Prefibrillar Amyloid Aggregates with Glutamatergic Receptors Results in Ca2+ Increase in Primary Neuronal Cells. J. Biol. Chem. 283 (44), 29950– 29960,  DOI: 10.1074/jbc.M803992200
    Google Scholar
    52
    Nonspecific Interaction of Prefibrillar Amyloid Aggregates with Glutamatergic Receptors Results in Ca2+ Increase in Primary Neuronal Cells
    Pellistri, Francesca; Bucciantini, Monica; Relini, Annalisa; Nosi, Daniele; Gliozzi, Alessandra; Robello, Mauro; Stefani, Massimo
    Journal of Biological Chemistry (2008), 283 (44), 29950-29960CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
    It is widely reported that the Ca2+ increase following nonspecific cell membrane permeabilization is among the earliest biochem. modifications in cells exposed to toxic amyloid aggregates. However, more recently receptors with Ca2+ channel activity such as α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), N-Me D-aspartate (NMDA), ryanodine, and inositol 1,4,5-trisphosphate receptors have been proposed as mediators of the Ca2+ increase in neuronal cells challenged with β-amyloid peptides. We previously showed that prefibrillar aggregates of proteins not assocd. with amyloid diseases are toxic to exposed cells similarly to comparable aggregates of disease-assocd. proteins. In particular, prefibrillar aggregates of the prokaryotic HypF-N were shown to be toxic to different cultured cell lines by eliciting Ca2+ and reactive oxygen species increases. This study was aimed at assessing whether NMDA and AMPA receptor activations could be considered a generic feature of cell interaction with amyloid aggregates rather than a specific effect of some aggregated protein. Therefore, we investigated whether NMDA and AMPA receptors were involved in the Ca2+ increase following exposure of rat cerebellar granule cells to HypF-N prefibrillar aggregates. We found that the intracellular Ca2+ increase was assocd. with the early activation of NMDA and AMPA receptors, although some nonspecific membrane permeabilization was also obsd. at longer times of exposure. This result matched a significant co-localization of the aggregates with both receptors on the plasma membrane. Our data support the possibility that glutamatergic channels are generic sites of interaction with the cell membrane of prefibrillar aggregates of different peptides and proteins as well as the key structures responsible for the resulting early membrane permeabilization to Ca2+.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXht1ynt7bM&md5=3450bdbfbcc79be0a3bd6efcfa9cb12c
  53. 53
    Salazar, S. V. and Strittmatter, S. M. (2017) Cellular Prion Protein as a Receptor for Amyloid-β Oligomers in Alzheimer’s Disease. Biochem. Biophys. Res. Commun. 483 (4), 1143– 1147,  DOI: 10.1016/j.bbrc.2016.09.062
    Google Scholar
    53
    Cellular prion protein as a receptor for amyloid-β oligomers in Alzheimer's disease
    Salazar, Santiago V.; Strittmatter, Stephen M.
    Biochemical and Biophysical Research Communications (2017), 483 (4), 1143-1147CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)
    Sol. oligomers of amyloid-beta (Aβo) are implicated by biochem. and genetic evidence as a trigger for Alzheimer's disease (AD) pathophysiol. A key step is Aβo interaction with the neuronal surface to initiate a cascade of altered signal transduction leading to synaptic dysfunction and damage. This review discusses neuronal cell surface mols. with high affinity selectively for oligomeric disease-assocd. states of Aβ, with a particular focus on the role of cellular prion protein (PrPC) in this process. Addnl. receptors may contribute to mediation of Aβo action, but PrPC appears to play a primary role in a no. of systems. The specificity of binding, the genetic necessity in mouse models of disease and downstream signaling pathways are considered. Signal transduction downstream of Aβo complexes with PrPC involves metabotropic glutamate receptor 5 (mGluR5), Fyn kinase and Pyk2 kinase, with deleterious effects on synaptic transmission and maintenance. Current data support the hypothesis that a substantial portion of Aβo toxicity in AD is mediated after initial interaction with PrPC on the neuronal surface. As such, the interaction of Aβo with PrPC is a potential therapeutic intervention site for AD.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsFCrsbfO&md5=ca66bd363a8321200220fab42dd8a539
  54. 54
    Haas, L. T. and Strittmatter, S. M. (2016) Oligomers of Amyloid β Prevent Physiological Activation of the Cellular Prion Protein-Metabotropic Glutamate Receptor 5 Complex by Glutamate in Alzheimer Disease. J. Biol. Chem. 291 (33), 17112– 17121,  DOI: 10.1074/jbc.M116.720664
    Google Scholar
    54
    Oligomers of amyloid β prevent physiological activation of the cellular prion protein-metabotropic glutamate receptor 5 complex by glutamate in Alzheimer disease
    Haas, Laura T.; Strittmatter, Stephen M.
    Journal of Biological Chemistry (2016), 291 (33), 17112-17121CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
    The dysfunction and loss of synapses in Alzheimer disease are central to dementia symptoms. We have recently demonstrated that pathol. Amyloid β oligomer (Aβo) regulates the assocn. between intracellular protein mediators and the synaptic receptor complex composed of cellular prion protein (PrPC) and metabotropic glutamate receptor 5 (mGluR5). Here we sought to det. whether Aβo alters the physiol. signaling of the PrPC-mGluR5 complex upon glutamate activation. We provide evidence that acute exposure to Aβo as well as chronic expression of familial Alzheimer disease mutant transgenes in model mice prevents protein-protein interaction changes of the complex induced by the glutamate analog 3,5-dihydroxyphenylglycine. We further show that 3,5-dihydroxyphenylglycine triggers the phosphorylation and activation of protein tyrosine kinase 2-β (PTK2B, also referred to as Pyk2) and of calcium/calmodulin-dependent protein kinase II in wild-type brain slices but not in Alzheimer disease transgenic brain slices or wild-type slices incubated with Aβo. This study further distinguishes two sep. Aβo-dependent signaling cascades, one dependent on extracellular Ca2+ and Fyn kinase activation and the other dependent on the release of Ca2+ from intracellular stores. Thus, Aβo triggers multiple distinct PrPC-mGluR5-dependent events implicated in neurodegeneration and dementia. We propose that targeting the PrPC-mGluR5 complex will reverse aberrant Aβo-triggered states of the complex to allow physiol. fluctuations of glutamate signaling.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslaktL3P&md5=b338b288603f6edc0d4b6ed1f615df82
  55. 55
    Abedini, A., Cao, P., Plesner, A., Zhang, J., He, M., Derk, J., Patil, S. A., Rosario, R., Lonier, J., Song, F. (2018) RAGE Binds Preamyloid IAPP Intermediates and Mediates Pancreatic β Cell Proteotoxicity. J. Clin. Invest. 128 (2), 682– 698,  DOI: 10.1172/JCI85210
    Google Scholar
    55
    RAGE binds preamyloid IAPP intermediates and mediates pancreatic β cell proteotoxicity
    Abedini Andisheh; Zhang Jinghua; He Meilun; Derk Julia; Patil Sachi A; Rosario Rosa; Lonier Jacqueline; Song Fei; Schmidt Ann Marie; Cao Ping; Raleigh Daniel P; Plesner Annette; Koh Hyunwook; Li Huilin
    The Journal of clinical investigation (2018), 128 (2), 682-698 ISSN:.
    Islet amyloidosis is characterized by the aberrant accumulation of islet amyloid polypeptide (IAPP) in pancreatic islets, resulting in β cell toxicity, which exacerbates type 2 diabetes and islet transplant failure. It is not fully clear how IAPP induces cellular stress or how IAPP-induced toxicity can be prevented or treated. We recently defined the properties of toxic IAPP species. Here, we have identified a receptor-mediated mechanism of islet amyloidosis-induced proteotoxicity. In human diabetic pancreas and in cellular and mouse models of islet amyloidosis, increased expression of the receptor for advanced glycation endproducts (RAGE) correlated with human IAPP-induced (h-IAPP-induced) β cell and islet inflammation, toxicity, and apoptosis. RAGE selectively bound toxic intermediates, but not nontoxic forms of h-IAPP, including amyloid fibrils. The isolated extracellular ligand-binding domains of soluble RAGE (sRAGE) blocked both h-IAPP toxicity and amyloid formation. Inhibition of the interaction between h-IAPP and RAGE by sRAGE, RAGE-blocking antibodies, or genetic RAGE deletion protected pancreatic islets, β cells, and smooth muscle cells from h-IAPP-induced inflammation and metabolic dysfunction. sRAGE-treated h-IAPP Tg mice were protected from amyloid deposition, loss of β cell area, β cell inflammation, stress, apoptosis, and glucose intolerance. These findings establish RAGE as a mediator of IAPP-induced toxicity and suggest that targeting the IAPP/RAGE axis is a potential strategy to mitigate this source of β cell dysfunction in metabolic disease.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MvhtVKntA%253D%253D&md5=e8bdc41817d48f49d22e4f4b3695b129
  56. 56
    Vogl, T., Leukert, N., Barczyk, K., Strupat, K., and Roth, J. (2006) Biophysical Characterization of S100A8 and S100A9 in the Absence and Presence of Bivalent Cations. Biochim. Biophys. Acta, Mol. Cell Res. 1763 (11), 1298– 1306,  DOI: 10.1016/j.bbamcr.2006.08.028
    Google Scholar
    56
    Biophysical characterization of S100A8 and S100A9 in the absence and presence of bivalent cations
    Vogl, Thomas; Leukert, Nadja; Barczyk, Katarzyna; Strupat, Kerstin; Roth, Johannes
    Biochimica et Biophysica Acta, Molecular Cell Research (2006), 1763 (11), 1298-1306CODEN: BBAMCO; ISSN:0167-4889. (Elsevier Ltd.)
    S100A8 and S100A9 are two proinflammatory mols. belonging to the S100 family of calcium-binding proteins. Common to all S100 proteins, S100A8 and S100A9 form non-covalently assocd. complexes which have been shown to exhibit different functional properties. Besides dimerization, recent research is focused on the importance of higher oligomeric structures of S100 proteins induced by bivalent cations. While S100A8/S100A9-heterodimers are formed in the absence of calcium, tetramerization is strictly calcium-dependent. Heterodimer formation is not a simple process and our biophys. analyses (FRET, ESI-MS) demonstrate that simply mixing both subunits is not sufficient to induce complex formation. Steps of denaturation/renaturation are necessary for the recombinant complex to show identical biophys. properties as S100A8/S100A9 obtained from granulocytes. In addn. to calcium, both proteins are able to bind zinc with high affinity. Here, we demonstrate for the first time by different biophys. methods (MALDI-MS, ESI-MS, fluorescence spectroscopy) that zinc-binding, like calcium, induces (S100A8/S100A9)2-tetramers. Using mass spectrometric investigations, we demonstrate that zinc triggers the formation of (S100A8/S100A9)2-tetramers by zinc-specific binding sites rather than by interactions with calcium-specific EF-hands. The zinc-induced tetramer is structurally very similar to the calcium-induced tetramer. Thus, like calcium, zinc acts as a regulatory factor in S100A8/S100A9-dependent signaling pathways.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xht1CnsLbK&md5=f4bc53c5e2577488e442d1034458f067
  57. 57
    Wang, C., Iashchishyn, I. A., Kara, J., Foderà, V., Vetri, V., Sancataldo, G., Marklund, M., and Morozova-Roche, L. A. (2019) Proinflammatory and Amyloidogenic S100A9 Induced by Traumatic Brain Injury in Mouse Model. Neurosci. Lett. 699, 199– 205,  DOI: 10.1016/j.neulet.2019.02.012
    Google Scholar
    57
    Proinflammatory and amyloidogenic S100A9 induced by traumatic brain injury in mouse model
    Wang, Chao; Iashchishyn, Igor A.; Kara, John; Fodera, Vito; Vetri, Valeria; Sancataldo, Giuseppe; Marklund, Niklas; Morozova-Roche, Ludmilla A.
    Neuroscience Letters (2019), 699 (), 199-205CODEN: NELED5; ISSN:0304-3940. (Elsevier Ireland Ltd.)
    Traumatic brain injury (TBI) represents a significant risk factor for development of neurodegenerative diseases such as Alzheimer's and Parkinson's. The S100A9-driven amyloid-neuroinflammatory cascade occurring during primary and secondary TBI events can serve as a mechanistic link between TBI and Alzheimer's as demonstrated recently in the human brain tissues. Here by using immunohistochem. in the controlled cortical impact TBI mouse model we have found pro-inflammatory S100A9 in the brain tissues of all mice on the first and third post-TBI days, while 70% of mice did not show any S100A9 presence on seventh post-TBI day similar to controls. This indicates that defensive mechanisms effectively cleared S100A9 in these mouse brain tissues during post-TBI recovery. By using sequential immunohistochem. we have shown that S100A9 was produced by both neuronal and microglial cells. However, Aβ peptide deposits characteristic for Alzheimer's disease were not detected in any post-TBI animals. On the first and third post-TBI days S100A9 was found to aggregate intracellularly into amyloid oligomers, similar to what was previously obsd. in human TBI tissues. Complementary, by using Rayleigh scatting, intrinsic fluorescence and at. force microscopy we demonstrated that in vitro S100A9 self-assembles into amyloid oligomers within minutes. Its amyloid aggregation is highly dependent on changes of environmental conditions such as variation of calcium levels, pH, temp. and redn./oxidn., which might be relevant to perturbation of cellular and tissues homeostasis under TBI. Present results demonstrate that S100A9 induction mechanisms in TBI are similar in mice and humans, emphasizing that S100A9 is an important marker of brain injury and therefore can be a potential therapeutic target.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXjtFOkurY%253D&md5=00ce57ce6592952a11a2f6a928d0cd73
  58. 58
    Kayed, R., Canto, I., Breydo, L., Rasool, S., Lukacsovich, T., Wu, J., Albay, R., Pensalfini, A., Yeung, S., Head, E. (2010) Conformation Dependent Monoclonal Antibodies Distinguish Different Replicating Strains or Conformers of Prefibrillar Aβ Oligomers. Mol. Neurodegener. 5 (1), 57,  DOI: 10.1186/1750-1326-5-57
    Google Scholar
    58
    Conformation dependent monoclonal antibodies distinguish different replicating strains or conformers of prefibrillar Aβ oligomers
    Kayed, Rakez; Canto, Isabel; Breydo, Leonid; Rasool, Suhail; Lukacsovich, Tamas; Wu, Jessica; Albay, Ricardo, III; Pensalfini, Anna; Yeung, Stephen; Head, Elizabeth; Marsh, J. Lawrence; Glabe, Charles
    Molecular Neurodegeneration (2010), 5 (), 57CODEN: MNOEAZ; ISSN:1750-1326. (BioMed Central Ltd.)
    Background: Age-related neurodegenerative diseases share a no. of important pathol. features, such as accumulation of misfolded proteins as amyloid oligomers and fibrils. Recent evidence suggests that sol. amyloid oligomers and not the insol. amyloid fibrils may represent the primary pathol. species of protein aggregates. Results: We have produced several monoclonal antibodies that specifically recognize prefibrillar oligomers and do not recognize amyloid fibrils, monomer or natively folded proteins. Like the polyclonal antisera, the individual monoclonals recognize generic epitopes that do not depend on a specific linear amino acid sequence, but they display distinct preferences for different subsets of prefibrillar oligomers. Immunol. anal. of a no. of different prefibrillar Aβ oligomer prepns. show that structural polymorphisms exist in Aβ prefibrillar oligomers that can be distinguished on the basis of their reactivity with monoclonal antibodies. Western blot anal. demonstrates that the conformers defined by the monoclonal antibodies have distinct size distributions, indicating that oligomer structure varies with size. The different conformational types of Aβ prefibrillar oligomers can serve as they serve as templates for monomer addn., indicating that they seed the conversion of Aβ monomer into more prefibrillar oligomers of the same type. Conclusions: These results indicate that distinct structural variants or conformers of prefibrillar Aβ oligomers exist that are capable of seeding their own replication. These conformers may be analogous to different strains of prions.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhs1ams7fE&md5=54b7c4aca24f41e66a682f2a78efc8e0
  59. 59
    Eilers, P. H. C. (2003) A Perfect Smoother. Anal. Chem. 75 (14), 3631– 3636,  DOI: 10.1021/ac034173t
    Google Scholar
    59
    A Perfect Smoother
    Eilers, Paul H. C.
    Analytical Chemistry (2003), 75 (14), 3631-3636CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    The A. Savitzky and M. Golay (1964) filter has several disadvantages. A very attractive alternative is a smoother based on penalized least squares, extending ideas presented by E. T. Whittaker (1923). This smoother is extremely fast, gives continuous control over smoothness, interpolates automatically, and allows fast leave-one-out cross-validation. It can be programmed in a few lines of Matlab code. Theory, implementation, and applications are presented.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXktFGqsLw%253D&md5=eba4aed2ebbf3e48bd80049d8e0ce165
  60. 60
    Wasylewski, Z., Koloczek, H., and Wasniowska, A. (1988) Fluorescence-Quenching-Resolved Spectroscopy of Proteins. Eur. J. Biochem. 172 (3), 719– 724,  DOI: 10.1111/j.1432-1033.1988.tb13948.x
    Google Scholar
    60
    Fluorescence-quenching-resolved spectroscopy of proteins
    Wasylewski, Zygmunt; Koloczek, Henryk; Wasniowska, Alicja
    European Journal of Biochemistry (1988), 172 (3), 719-24CODEN: EJBCAI; ISSN:0014-2956.
    A new procedure is described for using fluorescence-quenching data of tryptophan residues in proteins to resolve their fluorescence emission spectra. In this concept, the Stern-Volmer quenching plot is detd. at each particular emission wavelength and iterative nonlinear least-squares fitting procedure allowed to resolve the steady-state emission spectra into components. The resolved components, attributed to each of tryptophan residue, can be characterized by different accessibility to the quencher. The ability to resolve fluorescence emission spectra can be improved by using different kinds of efficient quenchers, which can selectively quench the emission of exposed or both exposed and buried fluorophores. The method was used to decomp. emission fluorescence spectra in 2-tryptophan-contg. proteins: horse liver dehydrogenase, sperm whale apomyoglobin, and metalloprotease from Staphylococcus aureus. The resolved spectra of alc. dehydrogenase and metalloprotease are in excellent agreement with those previously obtained by single-photon counting or phase methods. The method presented here is tech. simple and does not require expensive instrumentation.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1cXhsVKmt70%253D&md5=bb0cf515871a8a98d9b958cd066dde9e
  61. 61
    Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C., and Ferrin, T. E. (2004) UCSF Chimera-AVisualization Sytem for Exploratory Research and Analysis Vesrion. J. Comput. Chem. 25, 1605– 1612,  DOI: 10.1002/jcc.20084
    Google Scholar
    61
    UCSF Chimera-A visualization system for exploratory research and analysis
    Pettersen, Eric F.; Goddard, Thomas D.; Huang, Conrad C.; Couch, Gregory S.; Greenblatt, Daniel M.; Meng, Elaine C.; Ferrin, Thomas E.
    Journal of Computational Chemistry (2004), 25 (13), 1605-1612CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)
    The design, implementation, and capabilities of an extensible visualization system, UCSF Chimera, are discussed. Chimera is segmented into a core that provides basic services and visualization, and extensions that provide most higher level functionality. This architecture ensures that the extension mechanism satisfies the demands of outside developers who wish to incorporate new features. Two unusual extensions are presented: Multiscale, which adds the ability to visualize large-scale mol. assemblies such as viral coats, and Collab., which allows researchers to share a Chimera session interactively despite being at sep. locales. Other extensions include Multalign Viewer, for showing multiple sequence alignments and assocd. structures; ViewDock, for screening docked ligand orientations; Movie, for replaying mol. dynamics trajectories; and Vol. Viewer, for display and anal. of volumetric data. A discussion of the usage of Chimera in real-world situations is given, along with anticipated future directions. Chimera includes full user documentation, is free to academic and nonprofit users, and is available for Microsoft Windows, Linux, Apple Mac OS X, SGI IRIX, and HP Tru64 Unix from http://www.cgl.ucsf.edu/chimera/.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXmvVOhsbs%253D&md5=944b175f440c1ff323705987cf937ee7
  62. 62
    Miletić, V., Odorčić, I., Nikolić, P., and Svedružić, Ž. M. (2017) In Silico Design of the First DNA-Independent Mechanism-Based Inhibitor of Mammalian DNA Methyltransferase Dnmt1. PLoS One 12, e0174410  DOI: 10.1371/journal.pone.0174410
    Google Scholar
    62
    In silico design of the first DNA-independent mechanism-based inhibitor of mammalian DNA methyltransferase Dnmt1
    Miletic, Vedran; Odorcic, Ivica; Nikolic, Patrik; Svedruzic, Zeljko M.
    PLoS One (2017), 12 (4), e0174410/1-e0174410/21CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
    We use our earlier exptl. studies of the catalytic mechanism of DNA methyltransferases to prep. in silico a family of novel mechanism-based inhibitors of human Dnmt1. Highly specific inhibitors of DNA methylation can be used for anal. of human epigenome and for the creation of iPS cells. We describe a set of adenosyl-1-methyl-pyrimidin-2-one derivs. as novel mechanism based inhibitors of mammalian DNA methyltransferase Dnmt1. The inhibitors have been designed to bind simultaneously in the active site and the cofactor site and thus act as transition- state analogs. Mol. dynamics studies showed that the lead compd. can form between 6 to 9 binding interactions with Dnmt1. QM/MM anal. showed that the upon binding to Dnmt1 the inhibitor can form a covalent adduct with active site Cys1226 and thus act as a mechanism-based suicide-inhibitor. The inhibitor can target DNA-bond and DNAfree form of Dnmt1, however the suicide-inhibition step is more likely to happen when DNA is bound to Dnmt1. The validity of presented anal. is described in detail using 69 modifications in the lead compd. structure. In total 18 of the presented 69 modifications can be used to prep. a family of highly specific inhibitors that can differentiate even between closely related enzymes such as Dnmt1 and Dnmt3a DNA methyltransferases. Presented results can be used for prepn. of some highly specific and potent inhibitors of mammalian DNA methylation with specific pharmacol. properties.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsValsrbL&md5=e52a25b05645fb00f338b89d0193afa6
  63. 63
    Ruiz-Carmona, S., Alvarez-Garcia, D., Foloppe, N., Garmendia-Doval, A. B., Juhos, S., Schmidtke, P., Barril, X., Hubbard, R. E., and Morley, S. D. (2014) rDock: a Fast, Versatile and Open Source Program for Docking Ligands to Proteins and Nucleic Acids. PLoS Comput. Biol. 10, e1003571  DOI: 10.1371/journal.pcbi.1003571
    Google Scholar
    63
    rDock: a fast, versatile and open source program for docking ligands to proteins and nucleic acids
    Ruiz-Carmona, Sergio; Alvarez-Garcia, Daniel; Foloppe, Nicolas; Garmendia-Doval, A. Beatriz; Juhos, Szilveszter; Schmidtke, Peter; Barril, Xavier; Hubbard, Roderick E.; Morley, S. David
    PLoS Computational Biology (2014), 10 (4), e1003571/1-e1003571/7, 7 pp.CODEN: PCBLBG; ISSN:1553-7358. (Public Library of Science)
    Identification of chem. compds. with specific biol. activities is an important step in both chem. biol. and drug discovery. When the structure of the intended target is available, one approach is to use mol. docking programs to assess the chem. complementarity of small mols. with the target; such calcns. provide a qual. measure of affinity that can be used in virtual screening (VS) to rank order a list of compds. according to their potential to be active. rDock is a mol. docking program developed at Vernalis for high-throughput VS (HTVS) applications. Evolved from RiboDock, the program can be used against proteins and nucleic acids, is designed to be computationally very efficient and allows the user to incorporate addnl. constraints and information as a bias to guide docking. This article provides an overview of the program structure and features and compares rDock to two ref. programs, AutoDock Vina (open source) and Schrodinger's Glide (com.). In terms of computational speed for VS, rDock is faster than Vina and comparable to Glide. For binding mode prediction, rDock and Vina are superior to Glide. The VS performance of rDock is significantly better than Vina, but inferior to Glide for most systems unless pharmacophore constraints are used; in that case rDock and Glide are of equal performance. The program is released under the Lesser General Public License and is freely available for download, together with the manuals, example files and the complete test sets, at online.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsVGlsL%252FO&md5=e4cb786d6567fdc7f2a46f64955a9992
  64. 64
    Lee, J., Patel, D. S., Ståhle, J., Park, S. J., Kern, N. R., Kim, S., Lee, J., Cheng, X., Valvano, M. A., Holst, O. (2019) CHARMM-GUI Membrane Builder for Complex Biological Membrane Simulations with Glycolipids and Lipoglycans. J. Chem. Theory Comput. 15, 775– 786,  DOI: 10.1021/acs.jctc.8b01066
    Google Scholar
    64
    CHARMM-GUI Membrane Builder for Complex Biological Membrane Simulations with Glycolipids and Lipoglycans
    Lee, Jumin; Patel, Dhilon S.; Stahle, Jonas; Park, Sang-Jun; Kern, Nathan R.; Kim, Seonghoon; Lee, Joonseong; Cheng, Xi; Valvano, Miguel A.; Holst, Otto; Knirel, Yuriy A.; Qi, Yifei; Jo, Sunhwan; Klauda, Jeffery B.; Widmalm, Goran; Im, Wonpil
    Journal of Chemical Theory and Computation (2019), 15 (1), 775-786CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)
    Glycolipids (such as glycoglycerolipids, glycosphingolipids, and glycosylphosphatidylinositol) and lipoglycans (such as lipopolysaccharides (LPS), lipooligosaccharides (LOS), mycobacterial lipoarabinomannan, and mycoplasma lipoglycans) are typically found on the surface of cell membranes and play crucial roles in various cellular functions. Characterizing their structure and dynamics at the mol. level is essential to understand their biol. roles, but systematic generation of glycolipid and lipoglycan structures is challenging because of great variations in lipid structures and glycan sequences (i.e., carbohydrate types and their linkages). To facilitate the generation of all-atom glycolipid/LPS/LOS structures, we have developed Glycolipid Modeler and LPS Modeler in CHARMM-GUI (http://www.charmm-gui.org), a web-based interface that simplifies building of complex biol. simulation systems. In addn., we have incorporated these modules into Membrane Builder so that users can readily build a complex sym. or asym. biol. membrane system with various glycolipids and LPS/LOS. These tools are expected to be useful in innovative and novel glycolipid/LPS/LOS modeling and simulation research by easing tedious and intricate steps in modeling complex biol. systems and shall provide insight into structures, dynamics, and underlying mechanisms of complex glycolipid-/LPS-/LOS-contg. biol. membrane systems.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisVOitrbO&md5=a212a0bfce1818bc74f2b317eff3af93
  65. 65
    Sousa da Silva, A. W and Vranken, W. F (2012) ACPYPE-Antechamber Python Parser Interface. BMC Res. Notes 5, 367,  DOI: 10.1186/1756-0500-5-367
    Google Scholar
    65
    ACPYPE - AnteChamber PYthon Parser interfacE
    Sousa da Silva Alan W; Vranken Wim F
    BMC research notes (2012), 5 (), 367 ISSN:.
    BACKGROUND: ACPYPE (or AnteChamber PYthon Parser interfacE) is a wrapper script around the ANTECHAMBER software that simplifies the generation of small molecule topologies and parameters for a variety of molecular dynamics programmes like GROMACS, CHARMM and CNS. It is written in the Python programming language and was developed as a tool for interfacing with other Python based applications such as the CCPN software suite (for NMR data analysis) and ARIA (for structure calculations from NMR data). ACPYPE is open source code, under GNU GPL v3, and is available as a stand-alone application at http://www.ccpn.ac.uk/acpype and as a web portal application at http://webapps.ccpn.ac.uk/acpype. FINDINGS: We verified the topologies generated by ACPYPE in three ways: by comparing with default AMBER topologies for standard amino acids; by generating and verifying topologies for a large set of ligands from the PDB; and by recalculating the structures for 5 protein-ligand complexes from the PDB. CONCLUSIONS: ACPYPE is a tool that simplifies the automatic generation of topology and parameters in different formats for different molecular mechanics programmes, including calculation of partial charges, while being object oriented for integration with other applications.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38fitlWjtg%253D%253D&md5=60f750ba98c975374b351a39a1fa0ec4
  66. 66
    Kim, S., Lee, J., Jo, S., Brooks, C. L., 3rd, Lee, H. S., and Im, W. (2017) CHARMM-GUI Ligand Reader and Modeler for CHARMM Force Field Generation of Small Molecules. J. Comput. Chem. 38, 1879– 1886,  DOI: 10.1002/jcc.24829
    Google Scholar
    66
    CHARMM-GUI ligand reader and modeler for CHARMM force field generation of small molecules
    Kim, Seonghoon; Lee, Jumin; Jo, Sunhwan; Brooks, Charles L., III; Lee, Hui Sun; Im, Wonpil
    Journal of Computational Chemistry (2017), 38 (21), 1879-1886CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)
    Reading ligand structures into any simulation program is often nontrivial and time consuming, esp. when the force field parameters and/or structure files of the corresponding mols. are not available. To address this problem, we have developed Ligand Reader & Modeler in CHARMM-GUI. Users can upload ligand structure information in various forms (using PDB ID, ligand ID, SMILES, MOL/MOL2/SDF file, or PDB/mmCIF file), and the uploaded structure is displayed on a sketchpad for verification and further modification. Based on the displayed structure, Ligand Reader & Modeler generates the ligand force field parameters and necessary structure files by searching for the ligand in the CHARMM force field library or using the CHARMM general force field (CGenFF). In addn., users can define chem. substitution sites and draw substituents in each site on the sketchpad to generate a set of combinatorial structure files and corresponding force field parameters for throughput or alchem. free energy simulations. Finally, the output from Ligand Reader & Modeler can be used in other CHARMM-GUI modules to build a protein-ligand simulation system for all supported simulation programs, such as CHARMM, NAMD, GROMACS, AMBER, GENESIS, LAMMPS, Desmond, OpenMM, and CHARMM/OpenMM. Ligand Reader & Modeler is available as a functional module of CHARMM-GUI at http://www.charmm-gui.org/input/ligandrm.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnslKhtLk%253D&md5=3e872e011783f98bc14594d91bc142ef
  67. 67
    Van Der Spoel, D., Lindahl, E., Hess, B., Groenhof, G., Mark, A. E., and Berendsen, H. J. (2005) GROMACS: Fast, Flexible, and Free. J. Comput. Chem. 26, 1701– 1718,  DOI: 10.1002/jcc.20291
    Google Scholar
    67
    GROMACS: Fast, flexible, and free
    Van Der Spoel, David; Lindahl, Erik; Hess, Berk; Groenhof, Gerrit; Mark, Alan E.; Berendsen, Herman J. C.
    Journal of Computational Chemistry (2005), 26 (16), 1701-1718CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)
    This article describes the software suite GROMACS (Groningen MAchine for Chem. Simulation) that was developed at the University of Groningen, The Netherlands, in the early 1990s. The software, written in ANSI C, originates from a parallel hardware project, and is well suited for parallelization on processor clusters. By careful optimization of neighbor searching and of inner loop performance, GROMACS is a very fast program for mol. dynamics simulation. It does not have a force field of its own, but is compatible with GROMOS, OPLS, AMBER, and ENCAD force fields. In addn., it can handle polarizable shell models and flexible constraints. The program is versatile, as force routines can be added by the user, tabulated functions can be specified, and analyses can be easily customized. Nonequil. dynamics and free energy detns. are incorporated. Interfaces with popular quantum-chem. packages (MOPAC, GAMES-UK, GAUSSIAN) are provided to perform mixed MM/QM simulations. The package includes about 100 utility and anal. programs. GROMACS is in the public domain and distributed (with source code and documentation) under the GNU General Public License. It is maintained by a group of developers from the Universities of Groningen, Uppsala, and Stockholm, and the Max Planck Institute for Polymer Research in Mainz. Its Web site is http://www.gromacs.org.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXht1SlsbbO&md5=4aa71b1dc0b5b4978a88b0568245a265
  68. 68
    Cheung, Y. T., Lau, W. K., Yu, M. S., Lai, C. S., Yeung, S. C., So, K. F., and Chang, R. C. (2009) Effects of All-Trans-Retinoic Acid on Human SH-SY5Y Neuroblastoma as In Vitro Model in Neurotoxicity Research. NeuroToxicology 30 (1), 127– 135,  DOI: 10.1016/j.neuro.2008.11.001
    Google Scholar
    68
    Effects of all-trans-retinoic acid on human SH-SY5Y neuroblastoma as in vitro model in neurotoxicity research
    Cheung, Yuen-Ting; Lau, Way Kwok-Wai; Yu, Man-Shan; Lai, Cora Sau-Wan; Yeung, Sze-Chun; So, Kwok-Fai; Chang, Raymond Chuen-Chung
    NeuroToxicology (2009), 30 (1), 127-135CODEN: NRTXDN; ISSN:0161-813X. (Elsevier B.V.)
    Human neuroblastoma SH-SY5Y is a dopaminergic neuronal cell line which has been used as an in vitro model for neurotoxicity expts. Although the neuroblastoma is usually differentiated by all-trans-retinoic acid (RA), both RA-differentiated and undifferentiated SH-SY5Y cells have been used in neuroscience research. However, the changes in neuronal properties triggered by RA as well as the subsequent responsiveness to neurotoxins have not been comprehensively studied. Therefore, we aim to re-evaluate the differentiation property of RA on this cell line. We hypothesize that modulation of signaling pathways and neuronal properties during RA-mediated differentiation in SH-SY5Y cells can affect their susceptibility to neurotoxins. The differentiation property of RA was confirmed by showing an extensive outgrowth of neurites, increased expressions of neuronal nuclei, neuron specific enolase, synaptophysin and synaptic assocd. protein-97, and decreased expression of inhibitor of differentiation-1. While undifferentiated SH-SY5Y cells were susceptible to 6-OHDA and MPP+, RA-differentiation conferred SH-SY5Y cells higher tolerance, potentially by up-regulating survival signaling, including Akt pathway as inhibition of Akt removed RA-induced neuroprotection against 6-OHDA. As a result, the real toxicity cannot be revealed in RA-differentiated cells. Therefore, undifferentiated SH-SY5Y is more appropriate for studying neurotoxicity or neuroprotection in exptl. Parkinson's disease research.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtFeqsbw%253D&md5=c0fd9e12f367cc8258ce304212571828
  69. 69
    Nosi, D., Mercatelli, R., Chellini, F., Soria, S., Pini, A., Formigli, L., and Quercioli, F. (2013) A Molecular Imaging Analysis of Cx43 Association with Cdo During Skeletal Myoblast Differentiation. J. Biophotonics 6 (8), 612– 621,  DOI: 10.1002/jbio.201200063
    Google Scholar
    69
    A molecular imaging analysis of Cx43 association with Cdo during skeletal myoblast differentiation
    Nosi, Daniele; Mercatelli, Raffaella; Chellini, Flaminia; Soria, Silvia; Pini, Alessandro; Formigli, Lucia; Quercioli, Franco
    Journal of Biophotonics (2013), 6 (8), 612-621CODEN: JBOIBX; ISSN:1864-063X. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Cell-to-cell contacts are crucial for cell differentiation. The promyogenic cell surface protein, Cdo, functions as a component of multiprotein clusters to mediate cell adhesion signaling. Connexin 43, the main connexin forming gap junctions, also plays a key role in myogenesis. At least part of its effects is independent of the intercellular channel function, but the mechanisms underlying are unknown. Here, using multiple optical approaches, we provided the first evidence that Cx43 phys. interacts with Cdo to form dynamic complexes during myoblast differentiation, offering clues for considering this interaction a structural basis of the channel-independent function of Cx43.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1amu77P&md5=cd23bd3959355f60143523005ad14929

Cited By

Click to copy section linkSection link copied!

This article is cited by 22 publications.

  1. Bakri Alaziqi, Liam Beckitt, David J. Townsend, Jasmine Morgan, Rebecca Price, Alana Maerivoet, Jillian Madine, David Rochester, Geoffrey Akien, David A. Middleton. Characterization of Olive Oil Phenolic Extracts and Their Effects on the Aggregation of the Alzheimer’s Amyloid-β Peptide and Tau. ACS Omega 2024, 9 (30) , 32557-32578. https://doi.org/10.1021/acsomega.4c01281
  2. Efrat Naaman, Amanda Qarawani, Rony Ben-Zvi Elimelech, Michal Harel, Shahaf Sigal-Dror, Shadi Safuri, Vytautas Smirnovas, Ieva Baronaite, Nina V. Romanova, Ludmilla A. Morozova-Roche, Shiri Zayit-Soudry. The Surprising Nonlinear Effects of S100A9 Proteins in the Retina. ACS Chemical Neuroscience 2024, 15 (4) , 735-744. https://doi.org/10.1021/acschemneuro.3c00650
  3. Natalia-Maria Christopoulou, Vasiliki Mamoulaki, Aglaia Mitsiakou, Eleni Samolada, Despina P. Kalogianni, Theodore K. Christopoulos. Screening Method for the Visual Discrimination of Olive Oil from Other Vegetable Oils by a Multispecies DNA Sensor. Analytical Chemistry 2024, 96 (4) , 1803-1811. https://doi.org/10.1021/acs.analchem.3c05507
  4. Goro Nishide, Keesiang Lim, Maiki Tamura, Akiko Kobayashi, Qingci Zhao, Masaharu Hazawa, Toshio Ando, Noritaka Nishida, Richard W. Wong. Nanoscopic Elucidation of Spontaneous Self-Assembly of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Open Reading Frame 6 (ORF6) Protein. The Journal of Physical Chemistry Letters 2023, 14 (38) , 8385-8396. https://doi.org/10.1021/acs.jpclett.3c01440
  5. Vinod Kumar Meena, Vijay Kumar, Shivani Karalia, Garima, Monica Sundd. Ellagic Acid Modulates Uninduced as well as Mutation and Metal-Induced Aggregation of α-Synuclein: Implications for Parkinson’s Disease. ACS Chemical Neuroscience 2021, 12 (19) , 3598-3614. https://doi.org/10.1021/acschemneuro.1c00317
  6. Jiarui Zhao, Yuan Peng, Zhenfang Lin, Yulai Gong. Association between Mediterranean diet adherence and Parkinson's disease: a systematic review and meta-analysis. The Journal of nutrition, health and aging 2025, 29 (2) , 100451. https://doi.org/10.1016/j.jnha.2024.100451
  7. Qi Tian, Zhijie Li, Ziang Yan, Shengming Jiang, Xincan Zhao, Lei Wang, Mingchang Li. Inflammatory role of S100A8/A9 in the central nervous system non-neoplastic diseases. Brain Research Bulletin 2024, 218 , 111100. https://doi.org/10.1016/j.brainresbull.2024.111100
  8. Junyi Chen, Wen-Zhu Yang, Huilan Chen, Xiuxia Ding, Hongxu Chen, Cai-Hong Zhan, Zhigang Jin. Targeting protein aggregation: the promising application of polyoxometalates in neurodegenerative diseases. Inorganic Chemistry Frontiers 2024, 11 (21) , 7238-7255. https://doi.org/10.1039/D4QI01945H
  9. Manuela Leri, Dan Sun, Željko M. Svedružic, Darius Šulskis, Vytautas Smirnovas, Massimo Stefani, Ludmilla Morozova-Roche, Monica Bucciantini. Pro-inflammatory protein S100A9 targeted by a natural molecule to prevent neurodegeneration onset. International Journal of Biological Macromolecules 2024, 276 , 133838. https://doi.org/10.1016/j.ijbiomac.2024.133838
  10. Debojyoti Halder, Subham Das, Alex Joseph. An insight into structure-activity relationship of naturally derived biological macromolecules for the treatment of Alzheimer’s disease: a review. Journal of Biomolecular Structure and Dynamics 2024, 42 (12) , 6455-6471. https://doi.org/10.1080/07391102.2023.2230279
  11. Natalia-Maria Christopoulou, Eleftheria Figgou, Panagiotis Kalaitzis, Despina P. Kalogianni, Theodore K. Christopoulos. Multiallelic DNA sensors for molecular traceability of olive oil varietal origin. Sensors and Actuators B: Chemical 2024, 406 , 135423. https://doi.org/10.1016/j.snb.2024.135423
  12. Di Zhang, Juanli Zhang, Zhongying Ma, Qianwen Wu, Meiyou Liu, Tingting Fan, Likun Ding, Danjun Ren, Aidong Wen, Jingwen Wang. Luteoloside inhibits Aβ1–42 fibrillogenesis, disintegrates preformed fibrils, and alleviates amyloid-induced cytotoxicity. Biophysical Chemistry 2024, 306 , 107171. https://doi.org/10.1016/j.bpc.2023.107171
  13. Simone Filardo, Mattioli Roberto, Daniel Di Risola, Luciana Mosca, Marisa Di Pietro, Rosa Sessa. Olea europaea L-derived secoiridoids: Beneficial health effects and potential therapeutic approaches. Pharmacology & Therapeutics 2024, 254 , 108595. https://doi.org/10.1016/j.pharmthera.2024.108595
  14. Ines Lopez del Castillo, Laura Vegas-Gomez, Joana Loureiro, Ines Moreno-Gonzalez. Natural molecules in neuroprotection and neurotoxicity in neurodegenerative diseases. 2024, 3-28. https://doi.org/10.1016/B978-0-443-23763-8.00001-4
  15. Rimgailė Tamulytė, Evelina Jankaitytė, Zigmantas Toleikis, Vytautas Smirnovas, Marija Jankunec. Pro-inflammatory protein S100A9 alters membrane organization by dispersing ordered domains. Biochimica et Biophysica Acta (BBA) - Biomembranes 2023, 1865 (3) , 184113. https://doi.org/10.1016/j.bbamem.2022.184113
  16. Wei Wei, Shixu Wang, Chongchong Xu, Xuemei Zhou, Xinqing Lian, Lin He, Kuan Li. Gut microbiota, pathogenic proteins and neurodegenerative diseases. Frontiers in Microbiology 2022, 13 https://doi.org/10.3389/fmicb.2022.959856
  17. Vinod Kumar Meena, Vijay Kumar, Shivani Karalia, Rohit Singh Dangi, Monica Sundd. Structural and mechanistic insights into modulation of α-Synuclein fibril formation by aloin and emodin. Biochimica et Biophysica Acta (BBA) - General Subjects 2022, 1866 (7) , 130151. https://doi.org/10.1016/j.bbagen.2022.130151
  18. Yijing Tang, Dong Zhang, Xiong Gong, Jie Zheng. Repurposing of intestinal defensins as multi-target, dual-function amyloid inhibitors via cross-seeding. Chemical Science 2022, 13 (24) , 7143-7156. https://doi.org/10.1039/D2SC01447E
  19. Xing Ge, Tingting Yao, Chaoran Zhang, Qingqing Wang, Xuxu Wang, Li-Chun Xu. Human microRNA-4433 (hsa-miR-4443) Targets 18 Genes to be a Risk Factor of Neurodegenerative Diseases. Current Alzheimer Research 2022, 19 (7) , 511-522. https://doi.org/10.2174/1567205019666220805120303
  20. Basavaraj Vastrad, Chanabasayya Vastrad. Bioinformatics and next generation sequencing data analysis to identify key genes and pathways influencing in Parkinson’s disease. 2022https://doi.org/10.1101/2022.02.27.482208
  21. Masood Sadiq Butt, Urwa Tariq, Iahtisham‐Ul‐Haq, Ambreen Naz, Muhammad Rizwan. Neuroprotective effects of oleuropein: Recent developments and contemporary research. Journal of Food Biochemistry 2021, 45 (12) https://doi.org/10.1111/jfbc.13967
  22. Alma Jahić Mujkić, Magda Tušek Žnidarič, Selma Berbić, Eva Žerovnik. Synergy of the Inhibitory Action of Polyphenols Plus Vitamin C on Amyloid Fibril Formation: Case Study of Human Stefin B. Antioxidants 2021, 10 (9) , 1471. https://doi.org/10.3390/antiox10091471
  23. Lili Arabuli, Igor A. Iashchishyn, Nina V. Romanova, Greta Musteikyte, Vytautas Smirnovas, Himanshu Chaudhary, Željko M. Svedružić, Ludmilla A. Morozova-Roche. Co-Aggregation of S100A9 with DOPA and Cyclen-Based Compounds Manifested in Amyloid Fibril Thickening without Altering Rates of Self-Assembly. International Journal of Molecular Sciences 2021, 22 (16) , 8556. https://doi.org/10.3390/ijms22168556
Download PDF
Go to ACS Chemical Neuroscience
Get e-Alerts
Get e-Alerts

ACS Chemical Neuroscience

Cite this: ACS Chem. Neurosci. 2021, 12, 11, 1905–1918
Click to copy citationCitation copied!
https://doi.org/10.1021/acschemneuro.0c00828
Published May 12, 2021

Copyright © 2021 The Authors. Published by American Chemical Society. This publication is licensed under

CC-BY 4.0 .

Article Views

4351

Altmetric

-

Citations

22
Learn about these metrics

Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.

Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.

The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.

  • Abstract

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 1

    Figure 1. Schematic presentation of the chemical structure of oleuropein and oleuropein aglycon (OleA).

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 2

    Figure 2. Inhibition of S100A9 amyloid formation in the presence of increasing OleA concentrations observed by the ThT fluorescence assay and AFM. (A) S100A9 amyloid kinetics in the presence of increasing OleA concentrations monitored by the ThT assay. (B) Fitting of the initial parts of S100A9 amyloid kinetics with the nucleation-dependent polymerization model. (C) Ratios of the effective rate constants of S100A9 amyloid kinetics in the presence and absence of OleA (B0 is the effective rate constant in the absence of OleA, and B(c) is the rate constant at an OleA concentration of c). (D) Ratios of plateau intensities of S100A9 amyloid kinetics in the presence and absence of OleA (I0 is the plateau intensity in the absence of OleA, and I(c) is the plateau intensity at an OleA concentration of c). AFM images of S100A9 amyloid species without OleA and with increasing OleA concentrations after a 6 h (E–H) and 48 h (I–L) incubation, respectively. Amyloid fibril length distributions without OleA and with increasing OleA concentrations after a 6 h (M–P) and 48 h (Q–S) incubation, respectively, measured in AFM images. (T) Median length of S100A9 amyloid fibrils after a 6 h (black circles) and 48 h (red triangles) incubation, respectively, with increasing OleA concentrations. Molar ratios of S100A9 to OleA and the time of incubation are indicated in the figures. 100 μM S100A9, PBS, pH 7.4, and 42 °C. z-scale in the AFM images is indicated on the right with the bar color gradient from dark brown to light yellow. x,y-AFM scan sizes are 2 × 2 μm.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 3

    Figure 3. Preformed S100A9 fibrils disintegrated by OleA. (A) Decrease of ThT dye fluorescence upon the addition of OleA to S100A9 fibrils formed after a 48 h incubation. (B) AFM images of S100A9 fibrils without OleA. (C) AFM image of S100A9 aggregates after the addition of 137 μM OleA to the sample shown in (B). 75 μM S100A9 was subjected to fibrillation in PBS, pH 7.4, at 42 °C. Scan sizes are 2.5 × 2.5 μm.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 4

    Figure 4. Far-UV CD spectra of native and amyloid S100A9 and the OleA effect on them. Spectra were recorded at 25 °C at the following conditions: 75 μM S100A9 in all samples and 1:2 S100A9 to OleA molar ratio, if OleA is added. PBS, pH 7.4. S100A9 fibrils were formed during the 48 h incubation at 42 °C. Labeling of the samples is shown in the legend.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 5

    Figure 5. Interaction of native and amyloid S100A9 with OleA monitored by intrinsic fluorescence. Fluorescence spectra of native (A) and amyloid (B) S100A9 upon increasing concentrations of OleA. (C) Relative fluorescence intensities at the spectral maximum of native (blue triangles) and amyloid (red circles) S100A9 upon increasing OleA concentrations. Fitting curves are shown by solid lines in the corresponding color. The two binding site model is shown in the inset. (D) Shifts of fluorescence spectral maxima of native and amyloid S100A9 determined by the first derivative method upon increasing OleA concentrations shown in the same symbols as in (C). Four μM S100A9, PBS, pH 7.4, and 42 °C.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 6

    Figure 6. MD simulation of the interactions of native S100A9 with OleA. (A) Binding of one OleA molecule per subunit of S100A9 dimer. S100A9 monomers are shown by the ribbon diagram in yellow and green colors, respectively. The amino acid side chains of S100A9, which form binding interactions with OleA, are shown by cyan sticks. OleA molecules are shown by magenta sticks. OleA forms hydrogen bonds with Glu 52 and Arg 85 and π–π stacking interactions with Trp 88. (B) B-factor presentation of the S100A9 dimer backbone shows that OleA (in black sticks) binds to the protein site with low mobility (shown in blue). The loops with high mobility are shown by thicker tubes with a color gradient from yellow to red, corresponding to increasing mobility. (C) S100A9 dimer surface presentation in space filling and colors based on the polarity of the amino acid residues: hydrophilic residues, blue; hydrophobic residues, brown; residues with intermediate properties, white. OleA (shown by sticks) binds to a shallow hydrophobic cavity on the S100A9 surface. (D) Detailed presentation of the OleA orientation and binding interactions (presented in yellow) highlighting: π–π stacking between Trp 88 and OleA, hydrogen bonding between Arg 85 and the carbonyl oxygen of OleA, and the proximity between Glu 52 and the ester group of OleA. (E) Number of hydrogen bonds between each OleA molecule and S100A9 dimer. OleA molecules dissociate when the number of hydrogen bonds falls to zero. Hydrogen bonds were defined as the interactions between the polar groups with an angle of less than 20° and less than 3.0 Å distance. (F) Root mean square deviation (RMSD) values demonstrating the mobility of each OleA molecule and S100A9 dimer. Ligand dissociation results in the rapid increase in the RMSD values.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 7

    Figure 7. Cytotoxic effect of the S100A9 amyloids in the SH-SY5Y cells is mitigated by OleA. (A) Viability of SH-SY5Y cells measured by the MTT assay and (B) ROS levels in the SH-SY5Y cells measured by DCFDA fluorescence. Cells were exposed to 20 μM S100A9 samples for 24 h. S100A9 was added in either native or amyloid forms, which were incubated for 24 and 48 h in PBS, pH 7.4, at 42 °C, respectively, prior the addition to the cells. S100A9 to OleA molar ratios were 1:0, 1:1, 1:2, 1:5, and 1:10 as indicated along x-axis. The control corresponds to the untreated cells and is shown by a single black bar, where the absence of S100A9 and OleA is indicated as (0:0). The experimental bars corresponding to the addition of native S100A9 are shown in black, the addition of 24 h aged S100A9 amyloids are shown in gray, and the 48 h aged amyloids are shown in white. Error bars indicate the standard error of the mean of the independent experiments carried out in triplicate. ***p < 0.001 and **p < 0.01 versus control (0:0). °p < 0.05 and °°p < 0.01 versus cell viability in the presence of native or the corresponding aggregated S100A9 without OleA, i.e., molar ratio (1:0). (C) Confocal microscopy imaging of the intracellular free Ca2+ levels in the SH-SY5Y cells exposed for 10, 30, and 60 min to 20 μM S100A9 amyloids incubated for 48 h in the absence or in the presence of OleA at the molar ratios of S100A9 to OleA indicated in the figure. Scale bars are 14 μm in all images.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 8

    Figure 8. Immunolocalization of S100A9 aggregates on the SH-SY5Y plasma membrane. Confocal microscopy imaging of SH-SY5Y cells exposed for 24 h to 20 μM S100A9 aggregated for 48 h in the absence or in the presence of different molar ratios of S100A9 to OleA as indicated in the figures. The cell membranes were stained with Alexa 488-conjugated CTX-B (green fluorescence); cell nuclei were stained with Hoechst 33342 (blue fluorescence), and protein aggregates were stained with anti-S100A9 antibodies followed by treatment with Alexa 568-conjugated antirabbit secondary antibodies (red fluorescence). The mergence of the channels is shown in (A–D). Zoomed areas from (A–D) are shown in (E–H). FRET efficiency in those areas is shown in (I–L). (M) S100A9 do not bind to membrane rafts in the SH-SY5Y cells pretreated with an inhibitor of the GM1 synthesis as revealed by the lack of FRET efficiency. The control corresponds to the untreated cells. The SH-SY5Y cells were pretreated with 10 μM PDMD for 48 h (indicated as CTRL-PDMP) to reduce GM1 on the cell surface and then incubated for 24 h with 20 μM S100A9 fibrils (in monomer concentration). (N) Quantification of green fluorescence per cell, indicating the reduction of GM1 in cell membranes. Error bars indicate the standard error of three independent experiments. *p < 0.001 versus control.

    High Resolution Image
    Download MS PowerPoint Slide

  • References

    This article references 69 other publications.

    1. 1
      Akiyama, H., Barger, S., Barnum, S., Bradt, B., Bauer, J., Cole, G. M., Cooper, N. R., Eikelenboom, P., Emmerling, M., Fiebich, B. L. (2000) Inflammation and Alzheimer’s disease. Neurobiol. Aging 21 (3), 383– 421,  DOI: 10.1016/S0197-4580(00)00124-X
      1
      Inflammation and Alzheimer's disease
      Akiyama, H.; Barger, S.; Barnum, S.; Bradt, B.; Bauer, J.; Cole, G. M.; Cooper, N. R.; Eikelenboom, P.; Emmerling, M.; Fiebich, B. L.; Finch, C. E.; Frautschy, S.; Griffin, W. S. T.; Hampel, H.; Hull, M.; Landreth, G.; Lue, L.-F.; Mrak, R.; Mackenzie, I. R.; McGeer, P. L.; O'Banion, M. K.; Pachter, J.; Pasinetti, G.; Plata-Salaman, C.; Rogers, J.; Rydel, R.; Shen, Y.; Streit, W.; Strohmeyer, R.; Tooyoma, I.; Van Muiswinkel, F. L.; Veerhuis, R.; Walker, D.; Webster, S.; Wegrzyniak, B.; Wenk, G.; Wyss-Coray, T.
      Neurobiology of Aging (2000), 21 (3), 383-421CODEN: NEAGDO; ISSN:0197-4580. (Elsevier Science Inc.)
      A review, with 636 refs. Inflammation clearly occurs in pathol. vulnerable regions of the Alzheimer's disease (AD) brain, and it does so with the full complexity of local peripheral inflammatory responses. In the periphery, degenerating tissue and the deposition of highly insol. abnormal materials are classical stimulants of inflammation. Likewise, in the AD brain damaged neurons and neurites and highly insol. amyloid β peptide deposits and neurofibrillary tangles provide obvious stimuli for inflammation. Because these stimuli are discrete, microlocalized, and present from early preclin. to terminal stages of AD, local upregulation of complement, cytokines, acute-phase reactants, and other inflammatory mediators is also discrete, microlocalized, and chronic. Cumulated over many years, direct and bystander damage from AD inflammatory mechanisms is likely to exacerbate the very pathogenic processes that gave rise to it. Thus, animal models and clin. studies, although still in their infancy, strongly suggest that AD inflammation contributes to AD pathogenesis. By better understanding AD inflammatory and immunoregulatory processes, it should be possible to develop anti-inflammatory approaches that may not cure AD but will likely help slow the progression or delay the onset of this devastating disorder.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXktVSmt74%253D&md5=409a0ca2920ef2cba12474cb7d05f4aa
    2. 2
      Hardy, J. and Selkoe, D. J. (2002) The Amyloid Hypothesis of Alzheimer’ s Disease: Progress and Problems on the Road to Therapeutics. Science 297 (5580), 353,  DOI: 10.1126/science.1072994
      2
      The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics
      Hardy, John; Selkoe, Dennis J.
      Science (Washington, DC, United States) (2002), 297 (5580), 353-356CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
      A review. It has been more than 10 yr since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused by deposition of amyloid β-peptide (Aβ) in plaques in brain tissue. According to the amyloid hypothesis, accumulation of Aβ in the brain is the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary tangles contg. tau protein, is proposed to result from an imbalance between Aβ prodn. and Aβ clearance.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xls1Cju7s%253D&md5=f7b8db1bc6f13e85f887b73f3042e86e
    3. 3
      Zhu, S., Wang, J., Zhang, Y., He, J., Kong, J., Wang, J.-F., and Li, X.-M. (2017) The Role of Neuroinflammation and Amyloid in Cognitive Impairment in an APP/PS1 Transgenic Mouse Model of Alzheimer’s Disease. CNS Neurosci. Ther. 23 (4), 310– 320,  DOI: 10.1111/cns.12677
      3
      The role of neuroinflammation and amyloid in cognitive impairment in an APP/PS1 transgenic mouse model of Alzheimer's disease
      Zhu, Shenghua; Wang, Junhui; Zhang, Yanbo; He, Jue; Kong, Jiming; Wang, Jun-Feng; Li, Xin-Min
      CNS Neuroscience & Therapeutics (2017), 23 (4), 310-320CODEN: CNTNAB; ISSN:1755-5930. (Wiley-Blackwell)
      Aims : Both amyloid deposition and neuroinflammation appear in the early course of Alzheimer's disease (AD). However, the progression of neuroinflammation and its relationship with amyloid deposition and behavioral changes have not been fully elucidated. A better understanding the role of neuroinflammation in AD might extend our current knowledge to therapeutic intervention possibilities. Methods : This study systematically characterized changes in behavioral abnormalities in APP/PS1 transgenic mice. Brain pathol. measures were performed in post-mortem brain tissues of mice from 2 to 22 mo. Results : APP/PS1 mice exhibited significant memory deficits from 5 mo old, which were aggravated at the later stage of life. However, the degree of memory impairments reached a plateau at 12 mo. An early appearance of amyloid plaques was at 3 mo with a linear increase throughout the disease course. CD11b-pos. microglia and glial fibrillary acidic protein-(GFAP) pos. astrocytes were first detected at 3 mo with a close assocn. with amyloid plaques. Yet, the rate of changes in glial activation slowed down from 12 mo despite the steady increase in Aβ. Conclusion : These findings provided evidence that neuroinflammation might be involved in the development and progression of cognitive deficits in APP/PS1 mice, suggesting novel intervention and prevention strategies for AD.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXksFaktr8%253D&md5=34feee5613ff847c8e2615f444238bdc
    4. 4
      Demuro, A., Mina, E., Kayed, R., Milton, S. C., Parker, I., and Glabe, C. G. (2005) Calcium Dysregulation and Membrane Disruption as a Ubiquitous Neurotoxic Mechanism of Soluble Amyloid Oligomers. J. Biol. Chem. 280 (17), 17294– 17300,  DOI: 10.1074/jbc.M500997200
      4
      Calcium Dysregulation and Membrane Disruption as a Ubiquitous Neurotoxic Mechanism of Soluble Amyloid Oligomers
      Demuro, Angelo; Mina, Erene; Kayed, Rakez; Milton, Saskia C.; Parker, Ian; Glabe, Charles G.
      Journal of Biological Chemistry (2005), 280 (17), 17294-17300CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
      Increasing evidence suggests that amyloid peptides assocd. with a variety of degenerative diseases induce neurotoxicity in their intermediate oligomeric state, rather than as monomers or fibrils. To test this hypothesis and investigate the possible involvement of Ca2+ signaling disruptions in amyloid-induced cytotoxicity, the authors made homogeneous prepns. of disease-related amyloids (Aβ, prion, islet amyloid polypeptide, polyglutamine, and lysozyme) in various aggregation states and tested their actions on fluo-3-loaded SH-SY5Y cells. Application of oligomeric forms of all amyloids tested (0.6-6 μg ml-1) rapidly (∼5 s) elevated intracellular Ca2+, whereas equiv. amts. of monomers and fibrils did not. Ca2+ signals evoked by Aβ42 oligomers persisted after depletion of intracellular Ca2+ stores, and small signals remained in Ca2+-free medium, indicating contributions from both extracellular and intracellular Ca2+ sources. The increased membrane permeability to Ca2+ cannot be attributed to activation of endogenous Ca2+ channels, because responses were unaffected by the potent Ca2+-channel blocker cobalt (20 μm). Instead, observations that Aβ42 and other oligomers caused rapid cellular leakage of anionic fluorescent dyes point to a generalized increase in membrane permeability. The resulting unregulated flux of ions and mols. may provide a common mechanism for oligomer-mediated toxicity in many amyloidogenic diseases, with dysregulation of Ca2+ ions playing a crucial role because of their strong trans-membrane concn. gradient and involvement in cell dysfunction and death.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjsFOguro%253D&md5=bbecbaadfc5f74d42bd09f2cddcf5763
    5. 5
      Perry, V. H., Nicoll, J. A. R., and Holmes, C. (2010) Microglia in Neurodegenerative Disease. Nat. Rev. Neurol. 6 (4), 193– 201,  DOI: 10.1038/nrneurol.2010.17
      5
      Microglia in neurodegenerative disease
      Perry V Hugh; Nicoll James A R; Holmes Clive
      Nature reviews. Neurology (2010), 6 (4), 193-201 ISSN:.
      Microglia, the resident macrophages of the CNS, are exquisitely sensitive to brain injury and disease, altering their morphology and phenotype to adopt a so-called activated state in response to pathophysiological brain insults. Morphologically activated microglia, like other tissue macrophages, exist as many different phenotypes, depending on the nature of the tissue injury. Microglial responsiveness to injury suggests that these cells have the potential to act as diagnostic markers of disease onset or progression, and could contribute to the outcome of neurodegenerative diseases. The persistence of activated microglia long after acute injury and in chronic disease suggests that these cells have an innate immune memory of tissue injury and degeneration. Microglial phenotype is also modified by systemic infection or inflammation. Evidence from some preclinical models shows that systemic manipulations can ameliorate disease progression, although data from other models indicates that systemic inflammation exacerbates disease progression. Systemic inflammation is associated with a decline in function in patients with chronic neurodegenerative disease, both acutely and in the long term. The fact that diseases with a chronic systemic inflammatory component are risk factors for Alzheimer disease implies that crosstalk occurs between systemic inflammation and microglia in the CNS.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3c3kslyntw%253D%253D&md5=efb215a8a737c924905e7aa04a5b6706
    6. 6
      Paradisi, S., Sacchetti, B., Balduzzi, M., Gaudi, S., and Malchiodi-Albedi, F. (2004) Astrocyte Modulation of In Vitro β-Amyloid Neurotoxicity. Glia 46 (3), 252– 260,  DOI: 10.1002/glia.20005
      6
      Astrocyte modulation of in vitro beta-amyloid neurotoxicity
      Paradisi Silvia; Sacchetti Benedetto; Balduzzi Maria; Gaudi Simona; Malchiodi-Albedi Fiorella
      Glia (2004), 46 (3), 252-60 ISSN:0894-1491.
      In Alzheimer's disease brain, beta-amyloid (Abeta) deposition is accompanied by astrocyte activation, whose role in the pathogenesis of the disease is still unclear. To explore the subject, we compared Abeta neurotoxicity in pure hippocampal cultures and neuronal-astrocytic cocultures, where astrocytes conditioned neurons but were not in contact with them or Abeta. In the presence of astrocytes, neurons were protected from Abeta neurotoxicity. Neuritic dystrophy was reduced, synapses were partially preserved, and apoptosis was contrasted. The protection disappeared when astrocytes were also treated with Abeta, suggesting that Abeta-astrocyte interaction is deleterious for neurons. This was supported by comparing Abeta neurotoxicity in pure neurons and neurons grown on astrocytes. In this case, where astrocytes were also in contact with Abeta, neuritic damage was enhanced and expression of synaptic vesicle proteins decreased. Our results suggest that astrocytes can protect neurons from Abeta neurotoxicity, but when they interact with Abeta, the protection is undermined and neurotoxicity enhanced.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2c7lsVerug%253D%253D&md5=d8fce7b7e08c280b10ed9f8b444a8936
    7. 7
      Eikelenboom, P., Hoozemans, J. J., Veerhuis, R., van Exel, E., Rozemuller, A. J., and van Gool, W. A. (2012) Whether, When and How Chronic Inflammation Increases the Risk of Developing Late-onset Alzheimer’s Disease. Alzheimer's Res. Ther. 4 (3), 15– 15,  DOI: 10.1186/alzrt118
      7
      Whether, when and how chronic inflammation increases the risk of developing late-onset Alzheimer's disease
      Eikelenboom, Piet; Hoozemans, Jeroen J. M.; Veerhuis, Rob; van Exel, Eric; Rozemuller, Annemieke J. M.; van Gool, Willem A.
      Alzheimer's Research & Therapy (2012), 4 (3), 15CODEN: ARTLCD; ISSN:1758-9193. (BioMed Central Ltd.)
      A review. Neuropathol. studies have revealed the presence of a broad variety of inflammation-related proteins (complement factors, acute-phase proteins, pro-inflammatory cytokines) in Alzheimer's disease (AD) brains. These constituents of innate immunity are involved in several crucial pathogenic events of the underlying pathol. cascade in AD and recent studies have shown that innate immunity is involved in the etiol. of late-onset AD. Genome-wide assocn. studies have demonstrated gene loci that are linked to the complement system. Neuropathol. and exptl. studies indicate that fibrillar amyloid-β (Aβ) can activate the innate immunity-related CD14 and Toll-like receptor signaling pathways of glial cells for pro-inflammatory cytokine prodn. The prodn. capacity of this pathway is under genetic control and offspring with a parental history of late-onset AD have a higher prodn. capacity for pro-inflammatory cytokines. The activation of microglia by fibrillar Aβ deposits in the early preclin. stages of AD can make the brain susceptible later on for a second immune challenge leading to enhanced prodn. of pro-inflammatory cytokines. An example of a second immune challenge could be systemic inflammation in patients with preclin. AD. Prospective epidemiol. studies show that elevated serum levels of acute phase reactants can be considered as a risk factor for AD. Clin. studies suggest that peripheral inflammation increases the risk of dementia, esp. in patients with preexistent cognitive impairment and accelerates further deterioration in demented patients. The view that peripheral inflammation can increase the risk of dementia in older people provides scope for prevention.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xpt1ajurw%253D&md5=a2a92116ef2fb0e70170b35ee945713c
    8. 8
      Lim, S., Chun, Y., Lee, J. S., and Lee, S.-J. (2016) Neuroinflammation in Synucleinopathies. Brain Pathol. 26 (3), 404– 409,  DOI: 10.1111/bpa.12371
      8
      Neuroinflammation in Synucleinopathies
      Lim Somin; Chun Yewon; Lee Jun Sung; Lee Seung-Jae
      Brain pathology (Zurich, Switzerland) (2016), 26 (3), 404-9 ISSN:.
      The causes of most neurodegenerative diseases are attributed to multiple genetic and environmental factors interacting with one another. Above all, inflammation in the nervous system has been implicated in many neurodegenerative diseases. Still, the roles of neuroinflammation in disease mechanisms and the triggers of inflammatory responses in disease-inflicted brain tissues seem to remain unclear. This review will examine previous studies that had been done from genetic, pathological and epidemiological perspectives. These studies assess the involvement of neuroinflammation in synucleinopathies, a group of neurodegenerative diseases that are characterized by deposition of α-synuclein aggregates such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. The review will also discuss the role of α-synuclein aggregates in triggering inflammatory responses from glial cells. It is expected that a precise assessment of the roles and mechanisms of neuroinflammation in neurodegenerative diseases will pave the way for the development of disease-modifying drugs.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28jmslyjsw%253D%253D&md5=0db4eb9a45b73151df154d7ce22d55a9
    9. 9
      Wang, C., Iashchishyn, I. A., Pansieri, J., Nystrom, S., Klementieva, O., Kara, J., Horvath, I., Moskalenko, R., Rofougaran, R., Gouras, G. (2018) S100A9-Driven Amyloid-Neuroinflammatory Cascade in Traumatic Brain Injury as a Precursor State for Alzheimer’s Disease. Sci. Rep. 8, 12836,  DOI: 10.1038/s41598-018-31141-x
      9
      S100A9-Driven Amyloid-Neuroinflammatory Cascade in Traumatic Brain Injury as a Precursor State for Alzheimer's Disease
      Wang Chao; Iashchishyn Igor A; Pansieri Jonathan; Kara John; Horvath Istvan; Moskalenko Roman; Rofougaran Reza; Morozova-Roche Ludmilla A; Iashchishyn Igor A; Nystrom Sofie; Klementieva Oxana; Gouras Gunnar; Moskalenko Roman; Kovacs Gabor G; Shankar S K
      Scientific reports (2018), 8 (1), 12836 ISSN:.
      Pro-inflammatory and amyloidogenic S100A9 protein is an important contributor to Alzheimer's disease (AD) pathology. Traumatic brain injury (TBI) is viewed as a precursor state for AD. Here we have shown that S100A9-driven amyloid-neuroinflammatory cascade was initiated in TBI and may serve as a mechanistic link between TBI and AD. By analyzing the TBI and AD human brain tissues, we demonstrated that in post-TBI tissues S100A9, produced by neurons and microglia, becomes drastically abundant compared to Aβ and contributes to both precursor-plaque formation and intracellular amyloid oligomerization. Conditions implicated in TBI, such as elevated S100A9 concentration, acidification and fever, provide strong positive feedback for S100A9 nucleation-dependent amyloid formation and delay in its proteinase clearance. Consequently, both intracellular and extracellular S100A9 oligomerization correlated with TBI secondary neuronal loss. Common morphology of TBI and AD plaques indicated their similar initiation around multiple aggregation centers. Importantly, in AD and TBI we found S100A9 plaques without Aβ. S100A9 and Aβ plaque pathology was significantly advanced in AD cases with TBI history at earlier age, signifying TBI as a risk factor. These new findings highlight the detrimental consequences of prolonged post-TBI neuroinflammation, which can sustain S100A9-driven amyloid-neurodegenerative cascade as a specific mechanism leading to AD development.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3c3itlOitw%253D%253D&md5=f4623ac4ea93ef3ab98aa20a3c70f5cf
    10. 10
      Horvath, I., Iashchishyn, I. A., Moskalenko, R. A., Wang, C., Warmlander, S. K. T. S., Wallin, C., Graslund, A., Kovacs, G. G., and Morozova-Roche, L. A. (2018) Co-aggregation of Pro-inflammatory S100A9 with Alpha-Synuclein in Parkinson’s Disease: Ex Vivo and In Vitro Studies. J. Neuroinflammation 15, 172,  DOI: 10.1186/s12974-018-1210-9
      10
      Co-aggregation of pro-inflammatory S100A9 with α-synuclein in Parkinson's disease: ex vivo and in vitro studies
      Horvath, Istvan; Iashchishyn, Igor A.; Moskalenko, Roman A.; Wang, Chao; Waermlaender, Sebastian K. T. S.; Wallin, Cecilia; Graeslund, Astrid; Kovacs, Gabor G.; Morozova-Roche, Ludmilla A.
      Journal of Neuroinflammation (2018), 15 (), 172/1-172/16CODEN: JNOEB3; ISSN:1742-2094. (BioMed Central Ltd.)
      Background: Chronic neuroinflammation is a hallmark of Parkinson's disease (PD) pathophysiol., assocd. with increased levels of pro-inflammatory factors in PD brain tissues. The pro-inflammatory mediator and highly amyloidogenic protein S100A9 is involved in the amyloid-neuroinflammatory cascade in Alzheimer's disease. This is the first report on the co-aggregation of α-synuclein (α-syn) and S100A9 both in vitro and ex vivo in PD brain. Methods: Single and sequential immunohistochem., immunofluorescence, scanning electron and at. force (AFM) microscopies were used to analyze the ex vivo PD brain tissues for S100A9 and α-syn location and aggregation. In vitro studies revealing S100A9 and α-syn interaction and co-aggregation were conducted by NMR, CD, Thioflavin-T fluorescence, AFM, and surface plasmon resonance methods. Results: Co-localized and co-aggregated S100A9 and α-syn were found in 20% Lewy bodies and 77% neuronal cells in the substantia nigra; both proteins were also obsd. in Lewy bodies in PD frontal lobe (Braak stages 4-6). Lewy bodies were characterized by ca. 10-23 μm outer diam., with S100A9 and α-syn being co-localized in the same lamellar structures. S100A9 was also detected in neurons and blood vessels of the aged patients without PD, but in much lesser extent. In vitro S100A9 and α-syn were shown to interact with each other via the α-syn C-terminus with an apparent dissocn. const. of ca. 5 μM. Their co-aggregation occurred significantly faster and led to formation of larger amyloid aggregates than the self-assembly of individual proteins. S100A9 amyloid oligomers were more toxic than those of α-syn, while co-aggregation of both proteins mitigated the cytotoxicity of S100A9 oligomers. Conclusions: We suggest that sustained neuroinflammation promoting the spread of amyloidogenic S100A9 in the brain tissues may trigger the amyloid cascade involving α-syn and S100A9 and leading to PD, similar to the effect of S100A9 and Aβ co-aggregation in Alzheimer's disease. The finding of S100A9 involvement in PD may open a new avenue for therapeutic interventions targeting S100A9 and preventing its amyloid self-assembly in affected brain tissues.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFWgurrK&md5=713ff8fce99cbbd976b097ec98515dbc
    11. 11
      Wang, C., Klechikov, A. G., Gharibyan, A. L., Wärmländer, S. K. T. S., Jarvet, J., Zhao, L., Jia, X., Narayana, V. K., Shankar, S. K., Olofsson, A. (2014) The Role of Pro-inflammatory S100A9 in Alzheimer’s Disease Amyloid-neuroinflammatory Cascade. Acta Neuropathol. 127 (4), 507– 522,  DOI: 10.1007/s00401-013-1208-4
      11
      The role of pro-inflammatory S100A9 in Alzheimer's disease amyloid-neuroinflammatory cascade
      Wang, Chao; Klechikov, Alexey G.; Gharibyan, Anna L.; Waermlaender, Sebastian K. T. S.; Jarvet, Juri; Zhao, Lina; Jia, Xueen; Shankar, S. K.; Olofsson, Anders; Braennstroem, Thomas; Mu, Yuguang; Graeslund, Astrid; Morozova-Roche, Ludmilla A.
      Acta Neuropathologica (2014), 127 (4), 507-522CODEN: ANPTAL; ISSN:0001-6322. (Springer)
      Pro-inflammatory S100A9 protein is increasingly recognized as an important contributor to inflammation-related neurodegeneration. Here, we provide insights into S100A9 specific mechanisms of action in Alzheimer's disease (AD). Due to its inherent amyloidogenicity S100A9 contributes to amyloid plaque formation together with Aβ. In traumatic brain injury (TBI) S100A9 itself rapidly forms amyloid plaques, which were reactive with oligomer-specific antibodies, but not with Aβ and amyloid fibrillar antibodies. They may serve as precursor-plaques for AD, implicating TBI as an AD risk factor. S100A9 was obsd. in some hippocampal and cortical neurons in TBI, AD and non-demented aging. In vitro S100A9 forms neurotoxic linear and annular amyloids resembling Aβ protofilaments. S100A9 amyloid cytotoxicity and native S100A9 pro-inflammatory signaling can be mitigated by its co-aggregation with Aβ, which results in a variety of micron-scale amyloid complexes. NMR and mol. docking demonstrated transient interactions between native S100A9 and Aβ. Thus, abundantly present in AD brain pro-inflammatory S100A9, possessing also intrinsic amyloidogenic properties and ability to modulate Aβ aggregation, can serve as a link between the AD amyloid and neuroinflammatory cascades and as a prospective therapeutic target.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslymu7bF&md5=af7f01a5c3f6f24fc24aa907b72e9e43
    12. 12
      Pruenster, M., Vogl, T., Roth, J., and Sperandio, M. (2016) S100A8/A9: From Basic Science to Clinical Application. Pharmacol. Ther. 167, 120– 131,  DOI: 10.1016/j.pharmthera.2016.07.015
      12
      S100A8/A9: From basic science to clinical application
      Pruenster, Monika; Vogl, Thomas; Roth, Johannes; Sperandio, Markus
      Pharmacology & Therapeutics (2016), 167 (), 120-131CODEN: PHTHDT; ISSN:0163-7258. (Elsevier)
      Neutrophils and monocytes belong to the first line of immune defense cells and are recruited to sites of inflammation during infection or sterile injury. Both cells contain huge amts. of the heterodimeric protein S100A8/A9 in their cytoplasm. S100A8/A9 belongs to the Ca2 + binding S100 protein family and has recently gained a lot of interest as a crit. alarmin modulating the inflammatory response after its release (extracellular S100A8/A9) from neutrophils and monocytes. Extracellular S100A8/A9 interacts with the pattern recognition receptors Toll-like receptor 4 (TLR4) and Receptor for Advanced Glycation Endproducts (RAGE) promoting cell activation and recruitment. Besides its biol. function, S100A8/A9 (also known as myeloid related protein 8/14, MRP8/14) was identified as interesting biomarker to monitor disease activity in chronic inflammatory disorders including inflammatory bowel disease and rheumatoid arthritis. Furthermore, S100A8/A9 has been tested successfully in pre-clin. imaging studies to localize sites of infection or sterile injury. Finally, recent evidence using small mol. inhibitors for S100A8/A9 also suggests that blocking S100A8/A9 activity exerts beneficial effects on disease activity in animal models of autoimmune diseases including multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel disease. This review will provide a comprehensive and detailed overview into the structure and biol. function of S100A8/A9 and also will give an outlook in terms of diagnostic and therapeutic applications targeting S100A8/A9.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlWjurzJ&md5=99ce16a70a32600c9f393ae6bfef9b90
    13. 13
      Markowitz, J. and Carson, W. E., 3rd. (2013) Review of S100A9 Biology and Its Role in Cancer. Biochim. Biophys. Acta, Rev. Cancer 1835 (1), 100– 109,  DOI: 10.1016/j.bbcan.2012.10.003
      13
      Review of S100A9 biology and its role in cancer
      Markowitz, Joseph; Carson, William E.
      Biochimica et Biophysica Acta, Reviews on Cancer (2013), 1835 (1), 100-109CODEN: BBACEU; ISSN:0304-419X. (Elsevier B.V.)
      A review. S100A9 is a calcium binding protein with multiple ligands and post-translation modifications that is involved in inflammatory events and the initial development of the cancer cell through to the development of metastatic disease. This review has a threefold purpose: 1) describe the S100A9 structural elements important for its biol. activity, 2) describe the S100A9 biol. in the context of the immune system, and 3) illustrate the role of S100A9 in the development of malignancy via interactions with the immune system and other cellular processes.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVKqurzJ&md5=b417186ba1010bf09ea0e350e2acd708
    14. 14
      Schluesener, H. J., Kremsner, P. G., and Meyermann, R. (1998) Widespread Expression of MRP8 and MRP14 in Human Cerebral Malaria by Microglial Cells. Acta Neuropathol. 96 (6), 575– 580,  DOI: 10.1007/s004010050938
      14
      Widespread expression of MRP8 and MRP14 in human cerebral malaria by microglial cells
      Schluesener, H. J.; Kremsner, Peter G.; Meyermann, Richard
      Acta Neuropathologica (1998), 96 (6), 575-580CODEN: ANPTAL; ISSN:0001-6322. (Springer-Verlag)
      Human cerebral malaria (CM) is an often fatal infection. The cascades of signaling events resulting in tissue trauma and coma are only slowly becoming unraveled. Here the authors report that microglial cells, sensitive cellular sensors of threats to the central nervous system, in CM express the myeloid-related proteins MRP8 (S100A8) and MRP14 (S100A9), Ca2+-binding sensor proteins of activated monocytes. Surprisingly, microglial activation was widespread throughout the brain in white and gray matter and not limited to areas of petechial bleedings or sequestration of infected erythrocytes. Further, apoptosis/necrosis is prominent in CM; not only leukocytes appeared apoptotic, neurons also appeared damaged and DNA fragmentation was revealed by in situ nick translation. Thus, a prominent feature of human CM is activation of microglia, and anal. of these reactive microglia might further promote the authors' understanding of CM pathol. and guide development of future therapeutic intervention of the local reactive processes.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXmvFyitLo%253D&md5=4db5ed68a417b831c80894978e554c30
    15. 15
      Postler, E., Lehr, A., Schluesener, H., and Meyermann, R. (1997) Expression of the S-100 proteins MRP-8 and −14 in Ischemic Brain Lesions. Glia 19 (1), 27– 34,  DOI: 10.1002/(SICI)1098-1136(199701)19:1<27::AID-GLIA3>3.0.CO;2-7
      15
      Expression of the S-100 proteins MRP-8 and -14 in ischemic brain lesions
      Postler E; Lehr A; Schluesener H; Meyermann R
      Glia (1997), 19 (1), 27-34 ISSN:0894-1491.
      So far, microglial activation in cerebral ischemia has only been studied in different animal models. We have investigated the activation of microglial cells in human cerebral ischemia. As a marker for the activation of these "brain macrophages," we have used the macrophage inhibitor factor-related-proteins MRP-8 and MRP-14, which belong to the calcium binding S-100 protein family. The proteins can be detected on microglial cells in bacterial encephalitis and Alzheimer's disease but have so far not been studied in non-inflammatory diseases, in which microglial activation also occurs. Antibodies against MRP-8 and -14 detected ramified microglial cells within the first 3 days after cerebral infarction. Labeled cells were found selectively in the periinfarctional area. To support the notion that these cells belong to the locally activated resident microglial population, we studied their proliferation rate by staining the Ki-67 antigen with the antibody MIB-1. Double-labeling clearly showed that in the early phase of cerebral infarction microglial cells in the periinfarctional area express MRP-8 and -14 and also proliferate. Surprisingly, MRPs are expressed no longer than 3 days post infarction. This indicates that the activation of the resident microglia is an early step of tissue reaction after cerebral infarction. Additionally, we found evidence that microglial cells contribute to the population of phagocytes only during the first 3 days post infarction. The majority of lipid phagocytes found in the later stages are obviously recruited from the blood-borne macrophage pool.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2s7ktlGmtg%253D%253D&md5=b269af3ced945688d66f310da4d3e5dc
    16. 16
      Nagareddy, P. R., Murphy, A. J., Stirzaker, R. A., Hu, Y., Yu, S., Miller, R. G., Ramkhelawon, B., Distel, E., Westerterp, M., Huang, L.-S. (2013) Hyperglycemia Promotes Myelopoiesis and Impairs the Resolution of Atherosclerosis. Cell Metab. 17 (5), 695– 708,  DOI: 10.1016/j.cmet.2013.04.001
      16
      Hyperglycemia Promotes Myelopoiesis and Impairs the Resolution of Atherosclerosis
      Nagareddy, Prabhakara R.; Murphy, Andrew J.; Stirzaker, Roslynn A.; Hu, Yunying; Yu, Shiquing; Miller, Rachel G.; Ramkhelawon, Bhama; Distel, Emilie; Westerterp, Marit; Huang, Li-Shin; Schmidt, Ann Marie; Orchard, Trevor J.; Fisher, Edward A.; Tall, Alan R.; Goldberg, Ira J.
      Cell Metabolism (2013), 17 (5), 695-708CODEN: CMEEB5; ISSN:1550-4131. (Elsevier Inc.)
      Diabetes is a major risk factor for atherosclerosis. Although atherosclerosis is initiated by deposition of cholesterol-rich lipoproteins in the artery wall, the entry of inflammatory leukocytes into lesions fuels disease progression and impairs resoln. We show that diabetic mice have increased nos. of circulating neutrophils and Ly6-Chi monocytes, reflecting hyperglycemia-induced proliferation and expansion of bone marrow myeloid progenitors and release of monocytes into the circulation. Increased neutrophil prodn. of S100A8/S100A9, and its subsequent interaction with the receptor for advanced glycation end products on common myeloid progenitor cells, leads to enhanced myelopoiesis. Treatment of hyperglycemia reduces monocytosis, entry of monocytes into atherosclerotic lesions, and promotes regression. In patients with type 1 diabetes, plasma S100A8/S100A9 levels correlate with leukocyte counts and coronary artery disease. Thus, hyperglycemia drives myelopoiesis and promotes atherogenesis in diabetes.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnsVyqs7Y%253D&md5=ff11d96d88b7b22191ca54f90233b5d4
    17. 17
      Ma, L.-P., Haugen, E., Ikemoto, M., Fujita, M., Terasaki, F., and Fu, M. (2012) S100A8/A9 Complex as a New Biomarker in Prediction of Mortality in Elderly Patients with Severe Heart Failure. Int. J. Cardiol. 155 (1), 26– 32,  DOI: 10.1016/j.ijcard.2011.01.082
      17
      S100A8/A9 complex as a new biomarker in prediction of mortality in elderly patients with severe heart failure
      Ma Li-Ping; Haugen Espen; Ikemoto Masaki; Fujita Masatoshi; Terasaki Fumio; Fu Michael
      International journal of cardiology (2012), 155 (1), 26-32 ISSN:.
      BACKGROUND: S100A8/A9 complex is a new inflammation-related protein and has a positive correlation with C-reaction protein level. However its role in chronic heart failure (CHF) remains unclear. METHODS AND RESULTS: Circulating levels of S100A8/A9 complex and other biomarkers (IL-6, IL-8, TNF-α, and BNP) were measured in CHF (n = 54) and hypertensive without CHF (n = 31) as well as healthy subjects (n = 23), with follow up to 1480 days. During follow-up, cumulative mortality rate for CHF patients was 63%. Plasma levels of S100A8/A9 complex, IL-6, IL-8 and TNF-α were significantly higher in CHF than the hypertensive patients and healthy subjects. A significant positive correlation was found between S100A8/A9 complex and IL-6 and IL-8 respectively. Cox regression analysis showed that IL-6 and IL-8 were predictors for mortality for 6 months, and S100A8/A9 complex, IL-6, IL-8 and age were predictors for mortality for one year whereas BNP, TNF-α, IL-6 and IL-8 remained predictors for mortality for two years. A combination of S100A8/A9 complex and IL-6 provided powerful predictive value in mortality for both 6 and 12 months. CONCLUSIONS: S100A8/A9 complex is a useful biomarker as a predictor for one year mortality and its combination with IL-6 is able to provide additive prognostic information in this vulnerable heart failure population in the elderly.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC383gsFyiuw%253D%253D&md5=9e31f29e08d75738e968ef7fbe218022
    18. 18
      Swindell, W. R., Johnston, A., Xing, X., Little, A., Robichaud, P., Voorhees, J. J., Fisher, G., and Gudjonsson, J. E. (2013) Robust Shifts in S100A9 Expression with Aging: A Novel Mechanism for Chronic Inflammation. Sci. Rep. 3 (1), 1215,  DOI: 10.1038/srep01215
      18
      Robust shifts in S100a9 expression with aging: a novel mechanism for chronic inflammation
      Swindell, William R.; Johnston, Andrew; Xing, Xianying; Little, Andrew; Robichaud, Patrick; Voorhees, John J.; Fisher, Gary; Gudjonsson, Johann E.
      Scientific Reports (2013), 3 (), 1215, 13 pp.CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)
      The S100a8 and S100a9 genes encode a pro-inflammatory protein (calgranulin) that has been implicated in multiple diseases. However, involvement of S100a8/a9 in the basic mechanisms of intrinsic aging has not been established. In this study, we show that shifts in the abundance of S100a8 and S100a9 mRNA are a robust feature of aging in mammalian tissues, involving a range of cell types including the central nervous system. To identify transcription factors that control S100a9 expression, we performed a large-scale transcriptome anal. of 62 mouse and human cell types. We identified cell type-specific trends, as well as robust assocns. linking S100a9 coexpression to elevated frequency of ETS family motifs and in particular, to motifs recognized by the transcription factor SPI/PU.1. Sparse occurrence of SATB1 motifs was also a strong predictor of S100a9 coexpression. These findings offer support for a novel mechanism by which a SPI1/PU.1-S100a9 axis sustains chronic inflammation during aging.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXpvFWjt74%253D&md5=8ff1b1f10a81db6c7d8496626fc2c72b
    19. 19
      Iashchishyn, I. A., Sulskis, D., Nguyen Ngoc, M., Smirnovas, V., and Morozova-Roche, L. A. (2017) Finke–Watzky Two-Step Nucleation–Autocatalysis Model of S100A9 Amyloid Formation: Protein Misfolding as “Nucleation” Event. ACS Chem. Neurosci. 8 (10), 2152– 2158,  DOI: 10.1021/acschemneuro.7b00251
      19
      Finke-Watzky Two-Step Nucleation-Autocatalysis Model of S100A9 Amyloid Formation: Protein Misfolding as "Nucleation" Event
      Iashchishyn, Igor A.; Sulskis, Darius; Nguyen Ngoc, Mai; Smirnovas, Vytautas; Morozova-Roche, Ludmilla A.
      ACS Chemical Neuroscience (2017), 8 (10), 2152-2158CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
      Quant. kinetic anal. is crit. for understanding amyloid mechanisms. Here, we demonstrate the application of the generic Finke-Watzky (F-W; 1997, 2008) 2-step nucleation-autocatalytic growth model to concn.-dependent amyloid kinetics of proinflammatory α-helical S100A9 protein/calgranulin B at pH 7.4 and temps. of 37 and 42°. The model is based on 2 pseudo-elementary reaction steps applied without further anal. constraints and its treatment of S100A9 amyloid self-assembly demonstrates that initial misfolding and β-sheet formation, defined as a "nucleation" step, spontaneously takes place within individual S100A9 mols. at a higher rate than the subsequent fibrillar growth. The latter, described as an autocatalytic process, will proceed if misfolded amyloid-prone S100A9 is populated on a macroscopic time scale. Short lengths of S100A9 fibrils were consistent with the F-W model. The anal. of fibrillar length distribution by the Bekker-Doering model demonstrated independently that such distribution was solely detd. by slow fibril growth and that there was no fragmentation or secondary pathways decreasing fibrillar length.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1Cltb3P&md5=9e6270edc1a9e7e2d0277ab483d7f14f
    20. 20
      Yanamandra, K., Alexeyev, O., Zamotin, V., Srivastava, V., Shchukarev, A., Brorsson, A.-C., Tartaglia, G. G., Vogl, T., Kayed, R., Wingsle, G. (2009) Amyloid Formation by the Pro-inflammatory S100A8/A9 Proteins in the Ageing Prostate. PLoS One 4 (5), e5562– e5562,  DOI: 10.1371/journal.pone.0005562
      There is no corresponding record for this reference.
    21. 21
      Eremenko, E., Ben-Zvi, A., Morozova-Roche, L. A., and Raveh, D. (2013) Aggregation of Human S100A8 and S100A9 Amyloidogenic Proteins Perturbs Proteostasis in a Yeast Model. PLoS One 8 (3), e58218  DOI: 10.1371/journal.pone.0058218
      21
      Aggregation of human S100A8 and S100A9 amyloidogenic proteins perturbs proteostasis in a yeast model
      Eremenko, Ekaterina; Ben-Zvi, Anat; Morozova-Roche, Ludmilla A.; Raveh, Dina
      PLoS One (2013), 8 (3), e58218CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
      Amyloid aggregates of the calcium-binding EF-hand proteins S100A8 and S100A9 have been found in the corpora amylacea of patients with prostate cancer and may play a role in carcinogenesis. Here, the authors present a novel model system using the yeast Saccharomyces cerevisiae to study human S100A8 and S100A9 aggregation and toxicity. They found that S100A8, S100A9 and S100A8/9 cotransfomants form SDS-resistant non-toxic aggregates in yeast cells. Using fluorescently tagged proteins, the authors showed that S100A8 and S100A9 accumulate in foci. After prolonged induction, S100A8 foci localized to the cell vacuole, whereas the S100A9 foci remained in the cytoplasm when present alone, but entered the vacuole in cotransformants. Biochem. anal. of the proteins indicated that S100A8 and S100A9 alone or coexpressed together form amyloid-like aggregates in yeast. Expression of S100A8 and S100A9 in wild-type yeast did not affect cell viability, but these proteins were toxic when expressed on a background of unrelated metastable temp.-sensitive mutant proteins, Cdc53-1p, Cdc34-2p, Srp1-31p and Sec27-1p. This finding suggests that the expression and aggregation of S100A8 and S100A9 may limit the capacity of the cellular proteostasis machinery. To test this hypothesis, the authors screened a set of chaperone deletion mutants and found that reducing the levels of the heat-shock proteins Hsp104p and Hsp70p was sufficient to induce S100A8 and S100A9 toxicity. This result indicates that the chaperone activity of the Hsp104/Hsp70 bichaperone system in wild type cells is sufficient to reduce S100A8 and S100A9 amyloid toxicity and preserve cellular proteostasis. Expression of human S100A8 and S100A9 in yeast thus provides a novel model system for the study of the interaction of amyloid deposits with the proteostasis machinery.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXktlWjsrg%253D&md5=adb676af9433824aad66ff794da89062
    22. 22
      Horvath, I., Jia, X., Johansson, P., Wang, C., Moskalenko, R., Steinau, A., Forsgren, L., Wågberg, T., Svensson, J., Zetterberg, H., and Morozova-Roche, L. A. (2016) Pro-inflammatory S100A9 Protein as a Robust Biomarker Differentiating Early Stages of Cognitive Impairment in Alzheimer’s Disease. ACS Chem. Neurosci. 7 (1), 34– 39,  DOI: 10.1021/acschemneuro.5b00265
      22
      Pro-inflammatory S100A9 Protein as a Robust Biomarker Differentiating Early Stages of Cognitive Impairment in Alzheimer's Disease
      Horvath, Istvan; Jia, Xueen; Johansson, Per; Wang, Chao; Moskalenko, Roman; Steinau, Andreas; Forsgren, Lars; Waagberg, Thomas; Svensson, Johan; Zetterberg, Henrik; Morozova-Roche, Ludmilla A.
      ACS Chemical Neuroscience (2016), 7 (1), 34-39CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
      Pro-inflammatory protein S100A9 was established as a biomarker of dementia progression and compared with others such as Aβ1-42 and tau-proteins. CSF samples from 104 stringently diagnosed individuals divided into five subgroups were analyzed, including nondemented controls, stable mild cognitive impairment (SMCI), mild cognitive impairment due to Alzheimer's disease (MCI-AD), Alzheimer's disease (AD), and vascular dementia (VaD) patients. ELISA, dot-blotting, and electrochem. impedance spectroscopy were used as research methods. The S100A9 and Aβ1-42 levels correlated with each other: their CSF content decreased already at the SMCI stage and declined further under MCI-AD, AD, and VaD conditions. Immunohistochem. anal. also revealed involvement of both Aβ1-42 and S100A9 in the amyloid-neuroinflammatory cascade already during SMCI. Tau proteins were not yet altered in SMCI; however their contents increased during MCI-AD and AD, diagnosing later dementia stages. Thus, four biomarkers together, reflecting different underlying pathol. causes, can accurately differentiate dementia progression and also distinguish AD from VaD.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslyktbjM&md5=9a2362b63b01d23b69f4dd2b4e6c5c88
    23. 23
      Stefani, M. and Rigacci, S. (2014) Beneficial Properties of Natural Phenols: Highlight on Protection Against Pathological Conditions Associated with Amyloid Aggregation. BioFactors 40 (5), 482– 493,  DOI: 10.1002/biof.1171
      23
      Beneficial properties of natural phenols: Highlight on protection against pathological conditions associated with amyloid aggregation
      Stefani, Massimo; Rigacci, Stefania
      BioFactors (2014), 40 (5), 482-493CODEN: BIFAEU; ISSN:1872-8081. (Wiley-Blackwell)
      A review. Mediterranean and Asian diets are currently considered as the most healthy traditional feeding habits effective against risk of age-assocd., particularly cardiovascular and neurodegenerative, diseases. A common feature of these two regimens is the abundance of foods and beverages of plant origin (green tea, extra virgin olive oil, red wine, spices, berries, and arom. herbs) that are considered responsible for the obsd. beneficial effects. Epidemiol. data suggest that the phenolic component remarkably enriched in these foods plays an important role in reducing the incidence of amyloid diseases, pathol. conditions assocd. to tissue deposition of toxic protein aggregates responsible for progressive functional deterioration. Great effort is being spent to provide knowledge on the effects of several natural phenols in this context, moving from the test tube to animal models and, more slowly, to the patient's bed. An emerging feature that makes these mols. increasingly attractive for amyloid disease prevention and therapy is their wide spectrum of activity: recent pieces of evidence suggest that they can inhibit the prodn. of amyloidogenic peptides from precursors, increase antioxidant enzyme activity, activate autophagy and reduce inflammation. Our concept should than shift from considering natural phenols simply as antioxidants or, at the best, as amyloid aggregation inhibitors, to describing them as potentially multitargeting drugs. A main concern is the low bioavailability of such compds. and efforts aimed at improving it are underway, with encapsulation strategies being the most promising ones. © 2014 BioFactors, 40(5):482-493, 2014.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVWnsLfM&md5=6fe575d1bd7e30a74c54978a209a92f9
    24. 24
      Leri, M., Scuto, M., Ontario, M. L., Calabrese, V., Calabrese, E. J., Bucciantini, M., and Stefani, M. (2020) Healthy Effects of Plant Polyphenols: Molecular Mechanisms. Int. J. Mol. Sci. 21 (4), 1250,  DOI: 10.3390/ijms21041250
      24
      Healthy effects of plant polyphenols molecular mechanisms
      Leri, Manuela; Scuto, Maria; Ontario, Maria Laura; Calabrese, Vittorio; Calabrese, Edward J.; Bucciantini, Monica; Stefani, Massimo
      International Journal of Molecular Sciences (2020), 21 (4), 1250CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)
      The increasing extension in life expectancy of human beings in developed countries is accompanied by a progressively greater rate of degenerative diseases assocd. with lifestyle and aging, most of which are still waiting for effective, not merely symptomatic, therapies. Accordingly, at present, the recommendations aimed at reducing the prevalence of these conditions in the population are limited to a safer lifestyle including phys./mental exercise, a reduced caloric intake, and a proper diet in a convivial environment. The claimed health benefits of the Mediterranean and Asian diets have been confirmed in many clin. trials and epidemiol. surveys. These diets are characterized by several features, including low meat consumption, the intake of oils instead of fats as lipid sources, moderate amts. of red wine, and significant amts. of fresh fruit and vegetables. In particular, the latter have attracted popular and scientific attention for their content, though in reduced amts., of a no. of mols. increasingly investigated for their healthy properties. Among the latter, plant polyphenols have raised remarkable interest in the scientific community; in fact, several clin. trials have confirmed that many health benefits of the Mediterranean/Asian diets can be traced back to the presence of significant amts. of these mols., even though, in some cases, contradictory results have been reported, which highlights the need for further investigation. In light of the results of these trials, recent research has sought to provide information on the biochem., mol., epigenetic, and cell biol. modifications by plant polyphenols in cell, organismal, animal, and human models of cancer, metabolic, and neurodegenerative pathologies, notably Alzheimer's and Parkinson disease. The findings reported in the last decade are starting to help to decipher the complex relations between plant polyphenols and cell homeostatic systems including metabolic and redox equil., proteostasis, and the inflammatory response, establishing an increasingly solid mol. basis for the healthy effects of these mols. Taken together, the data currently available, though still incomplete, are providing a rationale for the possible use of natural polyphenols, or their mol. scaffolds, as nutraceuticals to contrast aging and to combat many assocd. pathologies.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhslGmt7%252FN&md5=8bfe06c440f984df718a7db0c12e74e0
    25. 25
      Rigacci, S., Guidotti, V., Bucciantini, M., Parri, M., Nediani, C., Cerbai, E., Stefani, M., and Berti, A. (2010) Oleuropein Aglycon Prevents Cytotoxic Amyloid Aggregation of Human Amylin. J. Nutr. Biochem. 21 (8), 726– 735,  DOI: 10.1016/j.jnutbio.2009.04.010
      25
      Oleuropein aglycon prevents cytotoxic amyloid aggregation of human amylin
      Rigacci, Stefania; Guidotti, Valentina; Bucciantini, Monica; Parri, Matteo; Nediani, Chiara; Cerbai, Elisabetta; Stefani, Massimo; Berti, Andrea
      Journal of Nutritional Biochemistry (2010), 21 (8), 726-735CODEN: JNBIEL; ISSN:0955-2863. (Elsevier)
      Pancreatic amyloid deposits of amylin are a hallmark of Type II diabetes and considerable evidence indicates that amylin oligomers are cytotoxic to β-cells. Many efforts are presently spent to find out naturally occurring mols., or to design synthetic ones, able to hinder amylin aggregation or to protect cells against aggregate cytotoxicity. In this context, a protective effect of some polyphenols against amyloid cytotoxicity was reported. Actually dietary polyphenols are endowed with multiple health benefits, and extra virgin olive oil is attracting increasing interest as a source of these substances. Here, we investigated the effects on amylin aggregation and cytotoxicity of the secoiridoid oleuropein aglycon, the main phenolic component of extra virgin olive oil. We found that oleuropein, when present during the aggregation of amylin, consistently prevented its cytotoxicity to RIN-5F pancreatic β-cells, as detd. by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide test and caspase-3 activity assay. A lack of interaction with the cell membrane of amylin aggregates grown in the presence of oleuropein was shown by fluorescence microscopy and synthetic lipid vesicle permeabilization. Moreover, our ThT assay, CD anal. and electron microscopy images suggested that oleuropein interferes with amylin aggregation, resulting in a different path skipping the formation of toxic pre-fibrillar aggregates. These results provide a mol. basis for some of the benefits potentially coming from extra virgin olive oil consumption and pave the way to further studies on the possible pharmacol. use of oleuropein to prevent or to slow down the progression of type II diabetes.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXptVamt78%253D&md5=8571339f9624289049a490f0e25d965a
    26. 26
      Leri, M., Nosi, D., Natalello, A., Porcari, R., Ramazzotti, M., Chiti, F., Bellotti, V., Doglia, S. M., Stefani, M., and Bucciantini, M. (2016) The Polyphenol Oleuropein Aglycone Hinders the Growth of Toxic Transthyretin Amyloid Assemblies. J. Nutr. Biochem. 30, 153– 166,  DOI: 10.1016/j.jnutbio.2015.12.009
      26
      The polyphenol Oleuropein aglycone hinders the growth of toxic transthyretin amyloid assemblies
      Leri, Manuela; Nosi, Daniele; Natalello, Antonino; Porcari, Riccardo; Ramazzotti, Matteo; Chiti, Fabrizio; Bellotti, Vittorio; Doglia, Silvia Maria; Stefani, Massimo; Bucciantini, Monica
      Journal of Nutritional Biochemistry (2016), 30 (), 153-166CODEN: JNBIEL; ISSN:0955-2863. (Elsevier)
      Transthyretin (TTR) is involved in a subset of familial or sporadic amyloid diseases including senile systemic amyloidosis (SSA), familial amyloid polyneuropathy and cardiomyopathy (FAP/FAC) for which no effective therapy has been found yet. These conditions are characterized by extracellular deposits primarily found in the heart parenchyma and in peripheral nerves whose main component are amyloid fibrils, presently considered the main culprits of cell sufferance. The latter are polymeric assemblies grown from misfolded TTR, either wt or carrying one out of many identified mutations. The recent introduction in the clin. practice of synthetic TTR-stabilizing mols. that reduce protein aggregation provides the rationale to search natural effective mols. able to interfere with TTR amyloid aggregation by hindering the appearance of toxic species or by favoring the growth of harmless aggregates. Here we carried out an in depth biophys. and morphol. study on the mol. features of the aggregation of wt- and L55P-TTR involved in SSA or FAP/FAC, resp., and on the interference with fibril aggregation, stability and toxicity to cardiac HL-1 cells to demonstrate the ability of Oleuropein aglycon (OleA), the main phenolic component of the extra virgin olive oil. We describe the mol. basis of such interference and the resulting redn. of TTR amyloid aggregate cytotoxicity. Our data offer the possibility to validate and optimize the use of OleA or its mol. scaffold to rationally design promising drugs against TTR-related pathologies that could enter a clin. exptl. phase.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xis1Gis7g%253D&md5=df648a9675770f47caa514e982d62264
    27. 27
      Rigacci, S., Guidotti, V., Bucciantini, M., Nichino, D., Relini, A., Berti, A., and Stefani, M. (2011) Aβ(1–42) Aggregates into Non-Toxic Amyloid Assemblies in the Presence of the Natural Polyphenol Oleuropein Aglycon. Curr. Alzheimer Res. 8 (8), 841– 852,  DOI: 10.2174/156720511798192682
      27
      Aβ(1-42) aggregates into non-toxic amyloid assemblies in the presence of the natural polyphenol oleuropein aglycon
      Rigacci, Stefania; Guidotti, Valentina; Bucciantini, Monica; Nichino, Daniela; Relini, Annalisa; Berti, Andrea; Stefani, Massimo
      Current Alzheimer Research (2011), 8 (8), 841-852CODEN: CARUBY; ISSN:1567-2050. (Bentham Science Publishers Ltd.)
      Amyloid aggregation starts with the initial misfolding of peptide/protein precursors, with subsequent structural rearrangement into oligomers and protofibrils; the latter eventually organize into fibrils with shared basic structural features, found deposited in amyloid diseases. Mounting evidence indicates early oligomers as the most toxic amyloid species; accordingly, the search of inhibitors of their growth is considered a promising target to prevent amyloid toxicity. We recently showed that oleuropein aglycon, a polyphenol abundant in the extra virgin olive oil, interferes with the aggregation of amylin (involved in type-2 diabetes), eliminating its cytotoxicity. Here we report that oleuropein aglycon also hinders amyloid aggregation of Aβ(1-42) and its cytotoxicity, suggesting a general effect of such polyphenol. In particular, by a wide panel of different spectroscopic, immunol., cell viability and imaging techniques we provide a more detailed description of Aβ(1-42) structural modifications arising in the presence of the inhibitor and the resulting cytotoxicity. We here report that the polyphenol eliminates the appearance of early toxic oligomers favoring the formation of stable harmless protofibrils, structurally different from the typical Aβ(1-42) fibrils. We also show that oleuropein aglycon is maximally effective when is present at the beginning of the aggregation process; furthermore, when added to pre-formed fibrils, it does not induce the release of toxic oligomers but, rather, neutralizes any residual toxicity possibly arising from the residual presence of traces of sol. oligomers and other toxic aggregates. The possible use of this polyphenol as anti-aggregation mol. is discussed in the light of these data.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhs1ShtrvN&md5=4280c13b299c367bc10a8e52145a8ffc
    28. 28
      Palazzi, L., Bruzzone, E., Bisello, G., Leri, M., Stefani, M., Bucciantini, M., and Polverino de Laureto, P. (2018) Oleuropein Aglycone Stabilizes the Monomeric α-Synuclein and Favours the Growth of Non-Toxic Aggregates. Sci. Rep. 8 (1), 8337,  DOI: 10.1038/s41598-018-26645-5
      28
      Oleuropein aglycone stabilizes the monomeric α-synuclein and favours the growth of non-toxic aggregates
      Palazzi Luana; Bisello Giovanni; Polverino de Laureto Patrizia; Bruzzone Elena; Leri Manuela; Stefani Massimo; Bucciantini Monica; Leri Manuela
      Scientific reports (2018), 8 (1), 8337 ISSN:.
      α-synuclein plays a key role in the pathogenesis of Parkinson's disease (PD); its deposits are found as amyloid fibrils in Lewy bodies and Lewy neurites, the histopathological hallmarks of PD. Amyloid fibrillation is a progressive polymerization path starting from peptide/protein misfolding and proceeding through the transient growth of oligomeric intermediates widely considered as the most toxic species. Consequently, a promising approach of intervention against PD might be preventing α-synuclein build-up, misfolding and aggregation. A possible strategy involves the use of small molecules able to slow down the aggregation process or to alter oligomer conformation favouring the growth of non-pathogenic species. Here, we show that oleuropein aglycone (OleA), the main olive oil polyphenol, exhibits anti-amyloidogenic power in vitro by interacting with, and stabilizing, α-synuclein monomers thus hampering the growth of on-pathway oligomers and favouring the growth of stable and harmless aggregates with no tendency to evolve into other cytotoxic amyloids. We investigated the molecular basis of such interference by both biophysical techniques and limited proteolysis; aggregate morphology was monitored by electron microscopy. We also found that OleA reduces the cytotoxicity of α-synuclein aggregates by hindering their binding to cell membrane components and preventing the resulting oxidative damage to cells.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MbhsFemtg%253D%253D&md5=e9bed4333ac2bf282a12dc0f4994ee47
    29. 29
      Leri, M., Natalello, A., Bruzzone, E., Stefani, M., and Bucciantini, M. (2019) Oleuropein Aglycone and Hydroxytyrosol Interfere Differently with Toxic Aβ1–42 Aggregation. Food Chem. Toxicol. 129, 1– 12,  DOI: 10.1016/j.fct.2019.04.015
      29
      Oleuropein aglycone and hydroxytyrosol interfere differently with toxic Aβ1-42 aggregation
      Leri, Manuela; Natalello, Antonino; Bruzzone, Elena; Stefani, Massimo; Bucciantini, Monica
      Food and Chemical Toxicology (2019), 129 (), 1-12CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)
      Oleuropein aglycon (OleA), the most abundant polyphenol in extra virgin olive oil (EVOO), and Hydroxythyrosol (HT), the OleA main metabolite, have attracted our interest due to their multitarget effects, including the interference with amyloid aggregation path. However, the mechanistic details of their anti-amyloid effect are not known yet. We report here a broad biophys. approach and cell biol. techniques that enabled us to characterize the different mol. mechanisms by which OleA and HT modulate the Aβ1-42 fibrillation, a main histopathol. feature of Alzheimer's disease (AD). In particular, OleA prevents the growth of toxic Aβ1-42 oligomers and blocks their successive growth into mature fibrils following its interaction with the peptide N-terminus, while HT speeds up harmless fibril formation. Our data demonstrate that, by stabilizing oligomers and fibrils, both polyphenols reduce their seeding activity and aggregate/membrane interaction on human neuroblastoma SH-SY5Y cells. These findings highlight the great potential of EVOO polyphenols and offer the possibility to validate and to optimize their use for possible AD prevention and therapy.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXnvF2ht7s%253D&md5=3863c374b1298e87ce4fb3add2a6419f
    30. 30
      Palazzi, L., Leri, M., Cesaro, S., Stefani, M., Bucciantini, M., and Polverino de Laureto, P. (2020) Insight into the Molecular Mechanism Underlying the Inhibition of α-Synuclein Aggregation by Hydroxytyrosol. Biochem. Pharmacol. 173, 113722,  DOI: 10.1016/j.bcp.2019.113722
      30
      Insight into the molecular mechanism underlying the inhibition of α-synuclein aggregation by hydroxytyrosol
      Palazzi, Luana; Leri, Manuela; Cesaro, Samuele; Stefani, Massimo; Bucciantini, Monica; Polverino de Laureto, Patrizia
      Biochemical Pharmacology (Amsterdam, Netherlands) (2020), 173 (), 113722CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)
      Parkinson's disease (PD) is the second most prevalent neurodegenerative disease in the elderly people. To date, drugs able to reverse the disease are not available; the gold std. is levodopa that only relieves clin. symptoms, yet with severe side effects after prolonged administration. Many efforts are underway to find alternative targets for PD prevention or treatment, the most promising being α-synuclein (Syn). Recently, we reported that oleuropein aglycon (OleA) interferes with amyloid aggregation of Syn both stabilizing its monomeric state and inducing the formation of harmless, off-pathway oligomers. This study is focused at describing the interaction between Syn and hydroxytyrosol (HT), the phenolic moiety and main metabolite of OleA, and the interferences with Syn aggregation by using biophys. and biol. techniques. Our results show that HT dose-dependently inhibits Syn aggregation and that covalent and non-covalent binding mediate HT-Syn interaction. HT does not modify the natively unfolded structure of Syn, rather, it stabilizes specific regions of the mol. leading to inhibition of protein fibrillation. Cellular assays showed that HT reduces the toxicity of Syn aggregates. Moreover, Syn aggregates interaction with the cell membrane, an important factor for prion-like properties of Syn on-pathway oligomers, was reduced in cells exposed to Syn aggregates grown in the presence of HT.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXit12ktL7F&md5=a4445287929f44b1f225758d549bf706
    31. 31
      Daccache, A., Lion, C., Sibille, N., Gerard, M., Slomianny, C., Lippens, G., and Cotelle, P. (2011) Oleuropein and Derivatives From Olives as Tau Aggregation Inhibitors. Neurochem. Int. 58 (6), 700– 707,  DOI: 10.1016/j.neuint.2011.02.010
      31
      Oleuropein and derivatives from olives as Tau aggregation inhibitors
      Daccache, Anthony; Lion, Cedric; Sibille, Nathalie; Gerard, Melanie; Slomianny, Christian; Lippens, Guy; Cotelle, Philippe
      Neurochemistry International (2011), 58 (6), 700-707CODEN: NEUIDS; ISSN:0197-0186. (Elsevier Ltd.)
      Tau isoforms constitute a family of microtubule-assocd. proteins that are mainly expressed in neurons of the central nervous system. They promote the assembly of tubulin monomers into microtubules and modulate their stability, thus playing a key structural role in the distal portion of axons. In Alzheimer's disease and related tauopathies, Tau aggregation into fibrillary tangles contributes to intraneuronal and glial lesions. We report herein the ability of three natural phenolic derivs. obtained from olives and derived food products to prevent such Tau fibrillization in vitro, namely hydroxytyrosol, oleuropein, and oleuropein aglycon. The latter was found to be more active than the ref. Tau aggregation inhibitor methylene blue on both wild-type and P301L Tau proteins, inhibiting fibrillization at low micromolar concns. These findings might provide further exptl. support for the beneficial nutritional properties of olives and olive oil as well as a chem. scaffold for the development of new drugs aiming at neurodegenerative tauopathies.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXksFGmtLw%253D&md5=94c9cf92c95514c8dc8b024f96d53ce2
    32. 32
      Leri, M., Oropesa-Nuñez, R., Canale, C., Raimondi, S., Giorgetti, S., Bruzzone, E., Bellotti, V., Stefani, M., and Bucciantini, M. (2018) Oleuropein Aglycone: A Polyphenol with Different Targets Against Amyloid Toxicity. Biochim. Biophys. Acta, Gen. Subj. 1862 (6), 1432– 1442,  DOI: 10.1016/j.bbagen.2018.03.023
      32
      Oleuropein aglycone: A polyphenol with different targets against amyloid toxicity
      Leri, Manuela; Oropesa-Nunez, Reiner; Canale, Claudio; Raimondi, Sara; Giorgetti, Sofia; Bruzzone, Elena; Bellotti, Vittorio; Stefani, Massimo; Bucciantini, Monica
      Biochimica et Biophysica Acta, General Subjects (2018), 1862 (6), 1432-1442CODEN: BBGSB3; ISSN:0304-4165. (Elsevier B.V.)
      Many data highlight the benefits of the Mediterranean diet and its main lipid component, extra-virgin olive oil (EVOO). EVOO contains many phenolic compds. that have been found effective against several aging- and lifestyle-related diseases, including neurodegeneration. Oleuropein, a phenolic secoiroid glycoside, is the main polyphenol in the olive oil. It has been reported that the aglycon form of Oleuropein (OleA) interferes in vitro and in vivo with amyloid aggregation of a no. of proteins/peptides involved in amyloid, particularly neurodegenerative, diseases avoiding the growth of toxic oligomers and displaying protection against cognitive deterioration. In this study, we carried out a cellular and biophys. study on the relationships between the effects of OleA on the aggregation and cell interactions of the D76N β2-microglobulin (D76N b2m) variant assocd. with a familial form of systemic amyloidosis with progressive bowel dysfunction and extensive visceral amyloid deposits. Our results indicate that OleA protection against D76N b2m cytotoxicity results from (i) a modification of the conformational and biophys. properties of its amyloid fibrils; (ii) a modification of the cell bilayer surface properties of exposed cells. This study reveals that OleA remodels not only D76N b2m aggregates but also the cell membrane interfering with the misfolded proteins-cell membrane assocn., in most cases an early event triggering amyloid-mediated cytotoxicity. The data provided in the present article focus on OleA protection, featuring this polyphenol as a promising plant mol. useful against amyloid diseases.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXmsVKitL4%253D&md5=e3762313d1252ea3bf5f2cd7a8361f18
    33. 33
      Rigacci, S., Miceli, C., Nediani, C., Berti, A., Cascella, R., Pantano, D., Nardiello, P., Luccarini, I., Casamenti, F., and Stefani, M. (2015) Oleuropein Aglycone Induces Autophagy via the AMPK/mTOR Signalling Pathway: A Mechanistic Insight. Oncotarget 6 (34), 35344– 35357,  DOI: 10.18632/oncotarget.6119
      33
      Oleuropein aglycone induces autophagy via the AMPK/mTOR signalling pathway: a mechanistic insight
      Rigacci Stefania; Miceli Caterina; Nediani Chiara; Berti Andrea; Cascella Roberta; Stefani Massimo; Pantano Daniela; Nardiello Pamela; Luccarini Ilaria; Casamenti Fiorella
      Oncotarget (2015), 6 (34), 35344-57 ISSN:.
      The healthy effects of plant polyphenols, some of which characterize the so-called Mediterranean diet, have been shown to arise from epigenetic and biological modifications resulting, among others, in autophagy stimulation. Our previous work highlighted the beneficial effects of oleuropein aglycone (OLE), the main polyphenol found in the extra virgin olive oil, against neurodegeneration both in cultured cells and in model organisms, focusing, in particular, autophagy activation. In this study we investigated more in depth the molecular and cellular mechanisms of autophagy induction by OLE using cultured neuroblastoma cells and an OLE-fed mouse model of amylod beta (Aβ) deposition. We found that OLE triggers autophagy in cultured cells through the Ca2+-CAMKKβ-AMPK axis. In particular, in these cells OLE induces a rapid release of Ca2+ from the SR stores which, in turn, activates CAMKKβ, with subsequent phosphorylation and activation of AMPK. The link between AMPK activation and mTOR inhibition was shown in the OLE-fed animal model in which we found that decreased phospho-mTOR immunoreactivity and phosphorylated mTOR substrate p70 S6K levels match enhanced phospho-AMPK levels, supporting the idea that autophagy activation by OLE proceeds through mTOR inhibition. Our results agree with those reported for other plant polyphenols, suggesting a shared molecular mechanism underlying the healthy effects of these substances against ageing, neurodegeneration, cancer, diabetes and other diseases implying autophagy dysfunction.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28zitlGmuw%253D%253D&md5=4ed55c7e2bd9c10917d22d132d6a7752
    34. 34
      Grossi, C., Rigacci, S., Ambrosini, S., Ed Dami, T., Luccarini, I., Traini, C., Failli, P., Berti, A., Casamenti, F., and Stefani, M. (2013) The Polyphenol Oleuropein Aglycone Protects TgCRND8Mice against Aß Plaque Pathology. PLoS One 8 (8), e71702  DOI: 10.1371/journal.pone.0071702
      34
      The polyphenol oleuropein aglycone protects TgCRND8 mice against Aβ plaque pathology
      Grossi, Cristina; Rigacci, Stefania; Ambrosini, Stefano; Ed Dami, Teresa; Luccarini, Ilaria; Traini, Chiara; Failli, Paola; Berti, Andrea; Casamenti, Fiorella; Stefani, Massimo
      PLoS One (2013), 8 (8), e71702CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
      The claimed beneficial effects of the Mediterranean diet include prevention of several age-related dysfunctions including neurodegenerative diseases and Alzheimer-like pathol. These effects have been related to the protection against cognitive decline assocd. with aging and disease by a no. of polyphenols found in red wine and extra virgin olive oil. The double transgenic TgCRND8 mice (overexpressing the Swedish and Indiana mutations in the human amyloid precursor protein), aged 1.5 and 4, and age-matched wild type control mice were used to examine in vivo the effects of 8 wk dietary supplementation of oleuropein aglycon (50 mg/kg of diet), the main polyphenol found in extra virgin olive oil. We report here that dietary supplementation of oleuropein aglycon strongly improves the cognitive performance of young/middle-aged TgCRND8 mice, a model of amyloid-β deposition, respect to age-matched littermates with un-supplemented diet. Immunofluorescence anal. of cerebral tissue in oleuropein aglycon-fed transgenic mice showed remarkably reduced β-amyloid levels and plaque deposits, which appeared less compact and "fluffy"; moreover, microglia migration to the plaques for phagocytosis and a remarkable redn. of the astrocyte reaction were evident. Finally, oleuropein aglycon-fed mice brain displayed an astonishingly intense autophagic reaction, as shown by the increase of autophagic markers expression and of lysosomal activity. Data obtained with cultured cells confirmed the latter evidence, suggesting mTOR regulation by oleuropein aglycon. Our results support, and provide mechanistic insights into, the beneficial effects against Alzheimer-assocd. neurodegeneration of a polyphenol enriched in the extra virgin olive oil, a major component of the Mediterranean diet.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtlamsrfI&md5=0cabef823648e2452389ed35a0320d17
    35. 35
      Luccarini, I., Pantano, D., Nardiello, P., Cavone, L., Lapucci, A., Miceli, C., Nediani, C., Berti, A., Stefani, M., and Casamenti, F. (2016) The Polyphenol Oleuropein Aglycone Modulates the PARP1-SIRT1 Interplay: An In Vitro and In Vivo Study. J. Alzheimer's Dis. 54 (2), 737– 750,  DOI: 10.3233/JAD-160471
      35
      The Polyphenol Oleuropein Aglycone Modulates the PARP1-SIRT1 Interplay: An In Vitro and In Vivo Study
      Luccarini, Ilaria; Pantano, Daniela; Nardiello, Pamela; Cavone, Leonardo; Lapucci, Andrea; Miceli, Caterina; Nediani, Chiara; Berti, Andrea; Stefani, Massimo; Casamenti, Fiorella; Cassano, Tommaso
      Journal of Alzheimer's Disease (2016), 54 (2), 737-750CODEN: JADIF9; ISSN:1387-2877. (IOS Press)
      Poly(ADP-ribose) polymerase-1 (PARP1) activation contributes to the cascade of events initiated by amyloid-β (Aβ) peptide eventually leading to cell death in Alzheimer's disease brain. A significant accumulation of PAR polymers and increase of PARP1 expression were detected in the cortex at the early (3.5 mo) and intermediate (6 mo) stage of Aβ deposition in the TgCRND8 mouse model. Our previous data highlighted the beneficial effects of oleuropein aglycon (OLE), the main polyphenol found in the olive oil, against neurodegeneration both in cultured cells and in model organisms. Here we found that 8-wk OLE treatment (50mg/kg of diet) to 6-mo-old TgCRND8 mice rescued to control values PARP1 activation and the levels of its product, PAR. In N2a neuroblastoma cells, PARP1 activation and PAR formation upon exposure to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were abolished by pretreatment for 24h with either OLE (100μM) or PARP inhibitors. A significant redn. of the NAD+ content, compared to controls, was found in N2a cells exposed to MNNG (100μM) for 90min; the latter was slightly attenuated by cell treatment for 24h with PJ-34 or with OLE. In vitro and in vivo, the OLE-induced redn. of PARP1 activation was paralleled by the overexpression of Sirtuin1 (SIRT1), and, in vivo, by a decrease of NF-κB and the pro-apoptotic marker p53. In N2a cells, we also found that OLE potentiates the MNNG-induced increase of Beclin1 levels. In conclusion, our data show that OLE treatment counteracts neuronal damage through modulation of the PARP1-SIRT1 interplay.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVyisrrN&md5=41ee6b88a89ab8643d3fa9cf6f5a723f
    36. 36
      LeVine, H. (1995) Thioflavine T Interaction with Amyloid β-sheet Structures. Amyloid 2 (1), 1– 6,  DOI: 10.3109/13506129509031881
      36
      Thioflavine T interaction with amyloid β-sheet structures
      LeVine, Harry III
      Amyloid (1995), 2 (1), 1-6CODEN: AIJIET; ISSN:1350-6129.
      Thioflavine T (ThT) interacts in tissue sections with amyloid deposits comprised of a variety of protein species giving a characteristic fluorescent complex. Binding of the dye to amyloid fibrils in suspension generates an amyloid-specific fluorescent signal. This interaction with amyloid fibrils formed from different polypeptides and proteins contg. antiparallel β-pleated sheet secondary structure is selective, occurring strongly with amyloid fibrils formed from insulin, transthyretin, polyglycine(I), Aβ(1-40), and weakly with β2-microglobulin. No fluorescence changes were seen with β-sheet fibrillar poly-L-lysine, islet amyloid peptide (20-29), or poly-L-serine. Native forms of transthyretin, insulin, β2-microglobulin, poly-L-lysine, Aβ(1-40), or several proteins contg. high percentages of β-sheet were also unreactive. The affinity of the amyloid fibrils for ThT varied: (apparent Kd's 0.033 - 10 μM; Amyloid A protein < insulin < ApoAII < polyglycine < transthyretin < Aβ(1-40)). The spectral changes induced by the different amyloid fibrils are qual. the same regardless of the pKd of the interaction with ThT or the identity of the amyloid fibrils, suggesting that the quaternary and secondary, but not the primary structure of the amyloid fibrils are important in forming the amyloid fibril-specific ThT species. Thus, Thioflavine T provides a useful tool for the investigation of amyloidogenesis in a variety of systems.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXlsFyhs7g%253D&md5=4e7b589b31c163fd215a025a16664d49
    37. 37
      Pansieri, J., Ostojić, L., Iashchishyn, I. A., Magzoub, M., Wallin, C., Wärmländer, S. K. T. S., Gräslund, A., Nguyen Ngoc, M., Smirnovas, V., Svedružić, Ž. (2019) Pro-Inflammatory S100A9 Protein Aggregation Promoted by NCAM1 Peptide Constructs. ACS Chem. Biol. 14 (7), 1410– 1417,  DOI: 10.1021/acschembio.9b00394
      37
      Pro-inflammatory S100A9 protein aggregation promoted by NCAM1 peptide constructs
      Pansieri, Jonathan; Ostojic, Lucija; Iashchishyn, Igor A.; Magzoub, Mazin; Wallin, Cecilia; Waermlaender, Sebastian K. T. S.; Graeslund, Astrid; Nguyen Ngoc, Mai; Smirnovas, Vytautas; Svedruzic, Zeljko; Morozova-Roche, Ludmilla A.
      ACS Chemical Biology (2019), 14 (7), 1410-1417CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
      Amyloid cascade and neuroinflammation are hallmarks of neurodegenerative diseases, and pro-inflammatory S100A9 protein is central to both of them. Here, we have shown that NCAM1 peptide constructs carrying polycationic sequences derived from Aβ peptide (KKLVFF) and PrP protein (KKRPKP) significantly promote the S100A9 amyloid self-assembly in a concn.-dependent manner by making transient interactions with individual S100A9 mols., perturbing its native structure and acting as catalysts. Since the individual mol. misfolding is a rate-limiting step in S100A9 amyloid aggregation, the effects of the NCAM1 construct on the native S100A9 are so crit. for its amyloid self-assembly. S100A9 rapid self-assembly into large aggregated clumps may prevent its amyloid tissue propagation, and by modulating S100A9 aggregation as a part of the amyloid cascade, the whole process may be effectively tuned.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtV2lsLjM&md5=994b31d58e7e135544a71406e5148697
    38. 38
      Ferrone, F. (1999) Analysis of Protein Aggregation Kinetics. In Amyloid, Prions, and Other Protein Aggregates, Methods in Enzymology, Vol. 309, pp 256– 274, Academic Press, New York. DOI: 10.1016/S0076-6879(99)09019-9 .
      There is no corresponding record for this reference.
    39. 39
      Pansieri, J., Iashchishyn, I. A., Fakhouri, H., Ostojić, L., Malisauskas, M., Musteikyte, G., Smirnovas, V., Schneider, M. M., Scheidt, T., Xu, C. K. (2020) Templating S100A9 Amyloids on Aβ Fibrillar Surfaces Revealed by Charge Detection Mass Spectrometry, Microscopy, Kinetic and Microfluidic Analyses. Chem. Sci. 11 (27), 7031– 7039,  DOI: 10.1039/C9SC05905A
      39
      Templating S100A9 amyloids on Aβ fibrillar surfaces revealed by charge detection mass spectrometry, microscopy, kinetic and microfluidic analyses
      Pansieri, Jonathan; Iashchishyn, Igor A.; Fakhouri, Hussein; Ostojic, Lucija; Malisauskas, Mantas; Musteikyte, Greta; Smirnovas, Vytautas; Schneider, Matthias M.; Scheidt, Tom; Xu, Catherine K.; Meisl, Georg; Knowles, Tuomas P. J.; Gazit, Ehud; Antoine, Rodolphe; Morozova-Roche, Ludmilla A.
      Chemical Science (2020), 11 (27), 7031-7039CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
      The mechanism of amyloid co-aggregation and its nucleation process are not fully understood in spite of extensive studies. Deciphering the interactions between proinflammatory S100A9 protein and Aβ42 peptide in Alzheimer's disease is fundamental since inflammation plays a central role in the disease onset. Here we use innovative charge detection mass spectrometry (CDMS) together with biophys. techniques to provide mechanistic insight into the co-aggregation process and differentiate amyloid complexes at a single particle level. Combination of mass and charge distributions of amyloids together with reconstruction of the differences between them and detailed microscopy reveals that co-aggregation involves templating of S100A9 fibrils on the surface of Aβ42 amyloids. Kinetic anal. further corroborates that the surfaces available for the Aβ42 secondary nucleation are diminished due to the coating by S100A9 amyloids, while the binding of S100A9 to Aβ42 fibrils is validated by a microfluidic assay. We demonstrate that synergy between CDMS, microscopy, kinetic and microfluidic analyses opens new directions in interdisciplinary research.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtFOqtrjM&md5=870909e223e6273b417714be73311647
    40. 40
      Lambert de Malezieu, M., Ferron, S., Sauvager, A., Courtel, P., Ramassamy, C., Tomasi, S., and Abasq, M.-L. (2019) UV-Vis Spectroelectrochemistry of Oleuropein, Tyrosol, and p-Coumaric Acid Individually and in an Equimolar Combination. Differences in LC-ESI-MS2 Profiles of Oxidation Products and Their Neuroprotective Properties. Biomolecules 9 (12), 802,  DOI: 10.3390/biom9120802
      40
      UV-vis spectroelectrochemistry of oleuropein, tyrosol, and p-coumaric acid individually and in an equimolar combination. Differences in LC-ESI-MS2 profiles of oxidation products and their neuroprotective properties
      Lambert de Malezieu, Morgane; Ferron, Solenn; Sauvager, Aurelie; Courtel, Patricia; Ramassamy, Charles; Tomasi, Sophie; Abasq, Marie-Laurence
      Biomolecules (2019), 9 (12), 802CODEN: BIOMHC; ISSN:2218-273X. (MDPI AG)
      Major phenolic compds. from olive oil (ArOH-EVOO), oleuropein (Ole), tyrosol (Tyr), and p-coumaric acid (p-Cou), are known for their antioxidant and neuroprotective properties. We previously demonstrated that their combination could potentiate their antioxidant activity in vitro and in cellulo. To further our knowledge of their electron-transfer properties, Ole, Tyr, and p-Cou underwent a spectroelectrochem. study, performed either individually or in equimolar mixts. Two mixts. (Mix and Mix-seq) were prepd. in order to det. whether distinct mols. could arise from their simultaneous or sequential oxidn. The comparison of Liq. Chromatog.-Electrospray Ionization-Tandem Mass Spectrometry (LC-ESI-MS2) profiles highlighted the presence of specific oxidized products found in the mixes. We hypothesized that they derived from the dimerization between Tyr and Ole or p-Cou, which have reacted either in their native or oxidized forms. Moreover, Ole regenerates when the Mix undergoes oxidn. Our study also showed significant neuroprotection by oxidized Ole and oxidized Mix against H2O2 toxicity on SK-N-SH cells, after 24 h of treatment with very low concns. (1 and 5 nM). This suggests the putative relevant role of oxidized Ole products to protect or delay neuronal death.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisVOisbzF&md5=bce247f0495156061750c7fcec67e4e5
    41. 41
      Chang, C. C., Khan, I., Tsai, K. L., Li, H., Yang, L. W., Chou, R. H., and Yu, C. (2016) Blocking the Interaction between S100A9 and RAGE V Domain using CHAPS Molecule: A novel route to Drug Development Against Cell Proliferation. Biochim. Biophys. Acta, Proteins Proteomics 1864 (11), 1558– 69,  DOI: 10.1016/j.bbapap.2016.08.008
      41
      Blocking the interaction between S100A9 and RAGE V domain using CHAPS molecule: A novel route to drug development against cell proliferation
      Chang, Chin-Chi; Khan, Imran; Tsai, Kun-Lin; Li, Hongchun; Yang, Lee-Wei; Chou, Ruey-Hwang; Yu, Chin
      Biochimica et Biophysica Acta, Proteins and Proteomics (2016), 1864 (11), 1558-1569CODEN: BBAPBW; ISSN:1570-9639. (Elsevier B.V.)
      Human S100A9 (Calgranulin B) is a Ca2+-binding protein, from the S100 family, that often presents as a homodimer in myeloid cells. It becomes an important mediator during inflammation once calcium binds to its EF-hand motifs. Human RAGE protein (receptor for advanced glycation end products) is one of the target-proteins. RAGE binds to a hydrophobic surface on S100A9. Interactions between these proteins trigger signal transduction cascades, promoting cell growth, proliferation, and tumorigenesis. Here, we present the soln. structure of mutant S100A9 (C3S) homodimer, detd. by multi-dimensional NMR expts. We further characterize the soln. interactions between mS100A9 and the RAGE V domain via NMR spectroscopy. CHAPS is a zwitterionic and non-denaturing mol. widely used for protein solubilizing and stabilization. We found out that CHAPS and RAGE V domain would interact with mS100A9 by using 1H-15N HSQC NMR titrns. Therefore, using the HADDOCK program, we superimpose two binary complex models mS100A9-RAGE V domain and mS100A9-CHAPS and demonstrate that CHAPS mols. could play a crucial role in blocking the interaction between mS100A9 and the RAGE V domain. WST-1 assay results also support the conclusion that CHAPS inhibits the bioactivity of mS100A9. This report will help to inform new drug development against cell proliferation.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtleitrrJ&md5=edf7f6363b5d98376e5294ef68a8fe16
    42. 42
      Ferrer, I., Blanco, R., Carmona, M., Puig, B., Ribera, R., Rey, M. J., and Ribalta, T. (2001) Prion Protein Expression in Senile Plaques in Alzheimer’s Disease. Acta Neuropathol. 101 (1), 49– 56,  DOI: 10.1007/s004010000271
      42
      Prion protein expression in senile plaques in Alzheimer's disease
      Ferrer, I.; Blanco, R.; Carmona, M.; Puig, B.; Ribera, R.; Rey, M. J.; Ribalta, T.
      Acta Neuropathologica (2001), 101 (1), 49-56CODEN: ANPTAL; ISSN:0001-6322. (Springer-Verlag)
      Prion protein (PrPC) is a glycolipid-anchored cell membrane sialoglycoprotein that localizes in presynaptic membranes. Since synapses are vulnerable to Alzheimer's disease (AD), the present study examines PrPC expression in senile plaques, one of the major structural abnormalities in AD, by single- and double-labeling immunohistochem. Punctate PrPC immunoreactivity is found in diffuse plaques, whereas isolated large coarse PrPC-pos. granules reminiscent of dystrophic neurites are obsd. in neuritic plaques. Finally, PrPC deposition also occurs as dense filamentous and amorphous ppts. in amyloid cores of senile plaques, but not in the walls of blood vessels with amyloid angiopathy. In contrast to PrPC, βA4-amyloid immunoreactivity is preserved and even enhanced following incubation of the tissue sections with proteinase K prior to immunohistochem., thus indicating no PrPC and βA4-amyloid cross-reactivity in dense amyloid cores of senile plaques. Punctate PrPC deposition in diffuse plaques is similar to that of synaptophysin, a synaptic vesicle-assocd. protein, as already reported in other studies. Immunopptn., electrophoresis and Western blot studies have shown that synaptophysin, amyloid precursor protein (APP) and βA4 do not co-ppt. with PrP. These results suggest that synaptophysin, APP and βA4 are likely not bound to PrP. PrPC accumulation in βA4-amyloid dense cores may be the consequence of the release of PrP into the extracellular space. Whether PrPC accumulation in the extracellular space is the result of impaired endocytosis and subsequent hydrolysis in the endosomal compartment, in contrast to normal degrdn. of PrPC, resulting from or occurring in parallel to abnormal APP degrdn., deserves further study.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXhtValurs%253D&md5=ad313fb97a3424f0f9f87f3af05b2e20
    43. 43
      Vogl, T., Eisenblätter, M., Völler, T., Zenker, S., Hermann, S., van Lent, P., Faust, A., Geyer, C., Petersen, B., Roebrock, K. (2014) Alarmin S100A8/S100A9 as a Biomarker for Molecular Imaging of Local Inflammatory Activity. Nat. Commun. 5 (1), 4593,  DOI: 10.1038/ncomms5593
      43
      Alarmin S100A8/S100A9 as a biomarker for molecular imaging of local inflammatory activity
      Vogl, Thomas; Eisenblaetter, Michel; Voeller, Tom; Zenker, Stefanie; Hermann, Sven; van Lent, Peter; Faust, Andreas; Geyer, Christiane; Petersen, Beatrix; Roebrock, Kirsten; Schaefers, Michael; Bremer, Christoph; Roth, Johannes
      Nature Communications (2014), 5 (), 4593CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)
      Inflammation has a key role in the pathogenesis of various human diseases. The early detection, localization and monitoring of inflammation are crucial for tailoring individual therapies. However, reliable biomarkers to detect local inflammatory activities and to predict disease outcome are still missing. Alarmins, which are locally released during cellular stress, are early amplifiers of inflammation. Here, using optical mol. imaging, we demonstrate that the alarmin S100A8/S100A9 serves as a sensitive local and systemic marker for the detection of even sub-clin. disease activity in inflammatory and immunol. processes like irritative and allergic contact dermatitis. In a model of collagen-induced arthritis, we use S100A8/S100A9 imaging to predict the development of disease activity. Furthermore, S100A8/S100A9 can act as a very early and sensitive biomarker in exptl. leishmaniasis for phagocyte activation linked to an effective Th1-response. In conclusion, the alarmin S100A8/S100A9 is a valuable and sensitive mol. target for novel imaging approaches to monitor clin. relevant inflammatory disorders on a mol. level.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitVaksLfN&md5=12a921b769ee55ecc080d53474332119
    44. 44
      Bucciantini, M., Calloni, G., Chiti, F., Formigli, L., Nosi, D., Dobson, C. M., and Stefani, M. (2004) Prefibrillar Amyloid Protein Aggregates Share Common Features of Cytotoxicity. J. Biol. Chem. 279 (30), 31374– 31382,  DOI: 10.1074/jbc.M400348200
      44
      Prefibrillar Amyloid Protein Aggregates Share Common Features of Cytotoxicity
      Bucciantini, Monica; Calloni, Giulia; Chiti, Fabrizio; Formigli, Lucia; Nosi, Daniele; Dobson, Christopher M.; Stefani, Massimo
      Journal of Biological Chemistry (2004), 279 (30), 31374-31382CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
      The intracellular free Ca2+ concn. and redox status of murine fibroblasts exposed to prefibrillar aggregates of the HypF N-terminal domain have been investigated in vitro and in vivo using a range of fluorescent probes. Aggregate entrance into the cytoplasm is followed by an early rise of reactive oxygen species and free Ca2+ levels and eventually by cell death. Such changes correlate directly with the viability of the cells and are not obsd. when cell are cultured in the presence of reducing agents or in Ca2+-free media. In addn., moderate cell stress following exposure to the aggregates was found to be fully reversible. The results show that the cytotoxicity of prefibrillar aggregates of HypF-N, a protein not assocd. with clin. disease, has the same fundamental origin as that produced by similar types of aggregates of proteins linked with specific amyloidoses. These findings suggest that misfolded proteinaceous aggregates stimulate generic cellular responses as a result of the exposure of regions of the structure (such as hydrophobic residues and the polypeptide main chain) that are buried in the normally folded proteins. They also support the idea that a higher no. of degenerative pathologies than previously known might be considered as protein deposition diseases.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXlslOrs7g%253D&md5=f0ab3f11b00cc2b8b23acb99069545e6
    45. 45
      Novitskaya, V., Bocharova, O. V., Bronstein, I., and Baskakov, I. V. (2006) Amyloid Fibrils of Mammalian Prion Protein Are Highly Toxic to Cultured Cells and Primary Neurons. J. Biol. Chem. 281 (19), 13828– 13836,  DOI: 10.1074/jbc.M511174200
      45
      Amyloid Fibrils of Mammalian Prion Protein Are Highly Toxic to Cultured Cells and Primary Neurons
      Novitskaya, Vera; Bocharova, Olga V.; Bronstein, Igor; Baskakov, Ilia V.
      Journal of Biological Chemistry (2006), 281 (19), 13828-13836CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
      A growing body of evidence indicates that small, sol. oligomeric species generated from a variety of proteins and peptides rather than mature amyloid fibrils are inherently highly cytotoxic. Here, we show for the first time that mature amyloid fibrils produced from full-length recombinant mammalian prion protein (rPrP) were highly toxic to cultured cells and primary hippocampal and cerebellar neurons. Fibrils induced apoptotic cell death in a time- and dose-dependent manner. The toxic effect of fibrils was comparable with that exhibited by sol. small β-oligomers generated from the same protein. Fibrils prepd. from insulin were not toxic, suggesting that the toxic effect was not solely due to the highly polymeric nature of the fibrillar form. The cell death caused by rPrP fibrils or β-oligomers was substantially reduced when expression of endogenous PrPC was down-regulated by small interfering RNAs. In opposition to the β-oligomer and amyloid fibrils of rPrP, the monomeric α-helical form of rPrP stimulated neurite out-growth and survival of neurons. These studies illustrated that both sol. β-oligomer and amyloid fibrils of the prion protein are intrinsically toxic and confirmed that endogenously expressed PrPC is required for mediating the toxicity of abnormally folded external PrP aggregates.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xkt1ymurY%253D&md5=7dd9e8722bc1997f4d260444248ddd58
    46. 46
      Canale, C., Oropesa-Nuñez, R., Diaspro, A., and Dante, S. (2018) Amyloid and Membrane Complexity: The Toxic Interplay Revealed by AFM. Semin. Cell Dev. Biol. 73, 82– 94,  DOI: 10.1016/j.semcdb.2017.08.046
      46
      Amyloid and membrane complexity: The toxic interplay revealed by AFM
      Canale, Claudio; Oropesa-Nunez, Reinier; Diaspro, Alberto; Dante, Silvia
      Seminars in Cell & Developmental Biology (2018), 73 (), 82-94CODEN: SCDBFX; ISSN:1084-9521. (Elsevier Ltd.)
      A review. Lipid membranes play a fundamental role in the pathol. development of protein misfolding diseases. Several pieces of evidence suggest that the lipid membrane could act as a catalytic surface for protein aggregation. Furthermore, a leading theory indicates the interaction between the cell membrane and misfolded oligomer species as the responsible for cytotoxicity, hence, for neurodegeneration in disorders such as Alzheimer's and Parkinson's disease. The definition of the mechanisms that drive the interaction between pathol. protein aggregates and plasma membrane is fundamental for the development of effective therapies for a large class of diseases. Atomic force microscopy (AFM) has been employed to study how amyloid aggregates affect the cell physiol. properties. Considerable efforts were spent to characterize the interaction with model systems, i.e., planar supported lipid bilayers, but some works also addressed the problem directly on living cells. Here, an overview of the main works involving the use of the AFM on both model system and living cells will be provided. Different kind of approaches will be presented, as well as the main results derived from the AFM anal.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFSmsL3J&md5=912b964f5577766e290127a998df02e5
    47. 47
      Walsh, P., Vanderlee, G., Yau, J., Campeau, J., Sim, V. L., Yip, C. M., and Sharpe, S. (2014) The Mechanism of Membrane Disruption by Cytotoxic Amyloid Oligomers Formed by Prion Protein (106–126) is Dependent on Bilayer Composition. J. Biol. Chem. 289 (15), 10419– 10430,  DOI: 10.1074/jbc.M113.515866
      47
      The Mechanism of Membrane Disruption by Cytotoxic Amyloid Oligomers Formed by Prion Protein(106-126) Is Dependent on Bilayer Composition
      Walsh, Patrick; Vanderlee, Gillian; Yau, Jason; Campeau, Jody; Sim, Valerie L.; Yip, Christopher M.; Sharpe, Simon
      Journal of Biological Chemistry (2014), 289 (15), 10419-10430CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
      The formation of fibrillar aggregates has long been assocd. with neurodegenerative disorders such as Alzheimer and Parkinson diseases. Although fibrils are still considered important to the pathol. of these disorders, it is now widely understood that smaller amyloid oligomers are the toxic entities along the misfolding pathway. One characteristic shared by the majority of amyloid oligomers is the ability to disrupt membranes, a commonality proposed to be responsible for their toxicity, although the mechanisms linking this to cell death are poorly understood. Here, we describe the phys. basis for the cytotoxicity of oligomers formed by the prion protein (PrP)-derived amyloid peptide PrP(106-126). We show that oligomers of this peptide kill several mammalian cells lines, as well as mouse cerebellar organotypic cultures, and we also show that they exhibit antimicrobial activity. Phys. perturbation of model membranes mimicking bacterial or mammalian cells was investigated using at. force microscopy, polarized total internal reflection fluorescence microscopy, and NMR spectroscopy. Disruption of anionic membranes proceeds through a carpet or detergent model as proposed for other antimicrobial peptides. By contrast, when added to zwitterionic membranes contg. cholesterol-rich ordered domains, PrP(106-126) oligomers induce a loss of domain sepn. and decreased membrane disorder. Loss of raft-like domains may lead to activation of apoptotic pathways, resulting in cell death. This work sheds new light on the phys. mechanisms of amyloid cytotoxicity and is the first to clearly show membrane type-specific modes of action for a cytotoxic peptide.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXmtlCnsbo%253D&md5=6e3cdf9ca126d6309eff637155f6ada0
    48. 48
      Leri, M., Bemporad, F., Oropesa-Nuñez, R., Canale, C., Calamai, M., Nosi, D., Ramazzotti, M., Giorgetti, S., Pavone, F. S., Bellotti, V. (2016) Molecular Insights into Cell Toxicity of a Novel Familial Amyloidogenic Variant of β2-microglobulin. J. Cell. Mol. Med. 20 (8), 1443– 1456,  DOI: 10.1111/jcmm.12833
      48
      Molecular insights into cell toxicity of a novel familial amyloidogenic variant of β2-microglobulin
      Leri, Manuela; Bemporad, Francesco; Oropesa-Nunez, Reinier; Canale, Claudio; Calamai, Martino; Nosi, Daniele; Ramazzotti, Matteo; Giorgetti, Sofia; Pavone, Francesco S.; Bellotti, Vittorio; Stefani, Massimo; Bucciantini, Monica
      Journal of Cellular and Molecular Medicine (2016), 20 (8), 1443-1456CODEN: JCMMC9; ISSN:1582-4934. (Wiley-Blackwell)
      The first genetic variant of β2-microglobulin (b2M) assocd. with a familial form of systemic amyloidosis has been recently described. The mutated protein, carrying a substitution of Asp at position 76 with an Asn (D76N b2M), exhibits a strongly enhanced amyloidogenic tendency to aggregate with respect to the wild-type protein. In this study, we characterized the D76N b2M aggregation path and performed an unprecedented anal. of the biochem. mechanisms underlying aggregate cytotoxicity. We showed that, contrarily to what expected from other amyloid studies, early aggregates of the mutant are not the most toxic species, despite their higher surface hydrophobicity. By modulating ganglioside GM1 content in cell membrane or synthetic lipid bilayers, we confirmed the pivotal role of this lipid as aggregate recruiter favoring their cytotoxicity. We finally obsd. that the aggregates bind to the cell membrane inducing an alteration of its elasticity (with possible functional unbalance and cytotoxicity) in GM1-enriched domains only, thus establishing a link between aggregate-membrane contact and cell damage.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1SmtL%252FI&md5=569e255a9a3564a7f0a53904b708a902
    49. 49
      Cicerale, S., Conlan, X. A., Sinclair, A. J., and Keast, R. S. J. (2008) Chemistry and Health of Olive Oil Phenolics. Crit. Rev. Food Sci. Nutr. 49 (3), 218– 236,  DOI: 10.1080/10408390701856223
      There is no corresponding record for this reference.
    50. 50
      Bucciantini, M., Nosi, D., Forzan, M., Russo, E., Calamai, M., Pieri, L., Formigli, L., Quercioli, F., Soria, S., Pavone, F. (2012) Toxic Effects of Amyloid Fibrils on Cell Membranes: The Importance of Ganglioside GM1. FASEB J. 26 (2), 818– 831,  DOI: 10.1096/fj.11-189381
      50
      Toxic effects of amyloid fibrils on cell membranes: the importance of ganglioside GM1
      Bucciantini, Monica; Nosi, Daniele; Forzan, Mario; Russo, Edda; Calamai, Martino; Pieri, Laura; Formigli, Lucia; Quercioli, Franco; Soria, Silvia; Pavone, Francesco; Savistchenko, Jimmy; Melki, Ronald; Stefani, Massimo
      FASEB Journal (2012), 26 (2), 818-831, 10.1096/fj.11-189381CODEN: FAJOEC; ISSN:0892-6638. (Federation of American Societies for Experimental Biology)
      The interaction of amyloid aggregates with the cell plasma membrane is currently considered among the basic mechanisms of neuronal dysfunction in amyloid neurodegeneration. We used amyloid oligomers and fibrils grown from the yeast prion Sup35p, responsible for the specific prion trait [PSI+], to investigate how membrane lipids modulate fibril interaction with the membranes of cultured H-END cells and cytotoxicity. Sup35p shares no homol. with endogenous mammalian polypeptide chains. Thus, the generic toxicity of amyloids and the mol. events underlying cell degeneration can be investigated without interference with analogous polypeptides encoded by the cell genome. Sup35 fibrils bound to the cell membrane without increasing its permeability to Ca2+. Fibril binding resulted in structural reorganization and aggregation of membrane rafts, with GM1 clustering and alteration of its mobility. Sup35 fibril binding was affected by GM1 or its sialic acid moiety, but not by cholesterol membrane content, with complete inhibition after treatment with fumonisin B1 or neuraminidase. Finally, cell impairment resulted from caspase-8 activation after Fas receptor translocation on fibril binding to the plasma membrane. Our observations suggest that amyloid fibrils induce abnormal accumulation and overstabilization of raft domains in the cell membrane and provide a reasonable, although not unique, mechanistic and mol. explanation for fibril toxicity.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XitFOnt7o%253D&md5=3e235091b37469527df80656e9941281
    51. 51
      Calamai, M. and Pavone, F. S. (2013) Partitioning and Confinement of GM1 Ganglioside induced by Amyloid Aggregates. FEBS Lett. 587 (9), 1385– 1391,  DOI: 10.1016/j.febslet.2013.03.014
      51
      Partitioning and confinement of GM1 ganglioside induced by amyloid aggregates
      Calamai, Martino; Pavone, Francesco S.
      FEBS Letters (2013), 587 (9), 1385-1391CODEN: FEBLAL; ISSN:0014-5793. (Elsevier B.V.)
      Growing evidence shows that GM1 ganglioside is involved in amyloid deposition and toxicity. By means of real-time single particle tracking, we show that amyloid oligomers and aggregates formed by Aβ1-42 and amylin, two peptides assocd., resp., with the development of Alzheimer's disease and type II diabetes, interact with GM1 and decrease dramatically its lateral diffusion on the plasma membrane of living neuroblastoma cells. The confinement of GM1, a constituent of membrane rafts involved in neuroprotection, at the level of both types of amyloid aggregates can interfere with cell signaling pathways and contribute to the loss of neuroprotection.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXltFCktL0%253D&md5=8a6120f6badbd0c18f63fd5ec3a1a42e
    52. 52
      Pellistri, F., Bucciantini, M., Relini, A., Nosi, D., Gliozzi, A., Robello, M., and Stefani, M. (2008) Nonspecific Interaction of Prefibrillar Amyloid Aggregates with Glutamatergic Receptors Results in Ca2+ Increase in Primary Neuronal Cells. J. Biol. Chem. 283 (44), 29950– 29960,  DOI: 10.1074/jbc.M803992200
      52
      Nonspecific Interaction of Prefibrillar Amyloid Aggregates with Glutamatergic Receptors Results in Ca2+ Increase in Primary Neuronal Cells
      Pellistri, Francesca; Bucciantini, Monica; Relini, Annalisa; Nosi, Daniele; Gliozzi, Alessandra; Robello, Mauro; Stefani, Massimo
      Journal of Biological Chemistry (2008), 283 (44), 29950-29960CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
      It is widely reported that the Ca2+ increase following nonspecific cell membrane permeabilization is among the earliest biochem. modifications in cells exposed to toxic amyloid aggregates. However, more recently receptors with Ca2+ channel activity such as α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), N-Me D-aspartate (NMDA), ryanodine, and inositol 1,4,5-trisphosphate receptors have been proposed as mediators of the Ca2+ increase in neuronal cells challenged with β-amyloid peptides. We previously showed that prefibrillar aggregates of proteins not assocd. with amyloid diseases are toxic to exposed cells similarly to comparable aggregates of disease-assocd. proteins. In particular, prefibrillar aggregates of the prokaryotic HypF-N were shown to be toxic to different cultured cell lines by eliciting Ca2+ and reactive oxygen species increases. This study was aimed at assessing whether NMDA and AMPA receptor activations could be considered a generic feature of cell interaction with amyloid aggregates rather than a specific effect of some aggregated protein. Therefore, we investigated whether NMDA and AMPA receptors were involved in the Ca2+ increase following exposure of rat cerebellar granule cells to HypF-N prefibrillar aggregates. We found that the intracellular Ca2+ increase was assocd. with the early activation of NMDA and AMPA receptors, although some nonspecific membrane permeabilization was also obsd. at longer times of exposure. This result matched a significant co-localization of the aggregates with both receptors on the plasma membrane. Our data support the possibility that glutamatergic channels are generic sites of interaction with the cell membrane of prefibrillar aggregates of different peptides and proteins as well as the key structures responsible for the resulting early membrane permeabilization to Ca2+.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXht1ynt7bM&md5=3450bdbfbcc79be0a3bd6efcfa9cb12c
    53. 53
      Salazar, S. V. and Strittmatter, S. M. (2017) Cellular Prion Protein as a Receptor for Amyloid-β Oligomers in Alzheimer’s Disease. Biochem. Biophys. Res. Commun. 483 (4), 1143– 1147,  DOI: 10.1016/j.bbrc.2016.09.062
      53
      Cellular prion protein as a receptor for amyloid-β oligomers in Alzheimer's disease
      Salazar, Santiago V.; Strittmatter, Stephen M.
      Biochemical and Biophysical Research Communications (2017), 483 (4), 1143-1147CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)
      Sol. oligomers of amyloid-beta (Aβo) are implicated by biochem. and genetic evidence as a trigger for Alzheimer's disease (AD) pathophysiol. A key step is Aβo interaction with the neuronal surface to initiate a cascade of altered signal transduction leading to synaptic dysfunction and damage. This review discusses neuronal cell surface mols. with high affinity selectively for oligomeric disease-assocd. states of Aβ, with a particular focus on the role of cellular prion protein (PrPC) in this process. Addnl. receptors may contribute to mediation of Aβo action, but PrPC appears to play a primary role in a no. of systems. The specificity of binding, the genetic necessity in mouse models of disease and downstream signaling pathways are considered. Signal transduction downstream of Aβo complexes with PrPC involves metabotropic glutamate receptor 5 (mGluR5), Fyn kinase and Pyk2 kinase, with deleterious effects on synaptic transmission and maintenance. Current data support the hypothesis that a substantial portion of Aβo toxicity in AD is mediated after initial interaction with PrPC on the neuronal surface. As such, the interaction of Aβo with PrPC is a potential therapeutic intervention site for AD.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsFCrsbfO&md5=ca66bd363a8321200220fab42dd8a539
    54. 54
      Haas, L. T. and Strittmatter, S. M. (2016) Oligomers of Amyloid β Prevent Physiological Activation of the Cellular Prion Protein-Metabotropic Glutamate Receptor 5 Complex by Glutamate in Alzheimer Disease. J. Biol. Chem. 291 (33), 17112– 17121,  DOI: 10.1074/jbc.M116.720664
      54
      Oligomers of amyloid β prevent physiological activation of the cellular prion protein-metabotropic glutamate receptor 5 complex by glutamate in Alzheimer disease
      Haas, Laura T.; Strittmatter, Stephen M.
      Journal of Biological Chemistry (2016), 291 (33), 17112-17121CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
      The dysfunction and loss of synapses in Alzheimer disease are central to dementia symptoms. We have recently demonstrated that pathol. Amyloid β oligomer (Aβo) regulates the assocn. between intracellular protein mediators and the synaptic receptor complex composed of cellular prion protein (PrPC) and metabotropic glutamate receptor 5 (mGluR5). Here we sought to det. whether Aβo alters the physiol. signaling of the PrPC-mGluR5 complex upon glutamate activation. We provide evidence that acute exposure to Aβo as well as chronic expression of familial Alzheimer disease mutant transgenes in model mice prevents protein-protein interaction changes of the complex induced by the glutamate analog 3,5-dihydroxyphenylglycine. We further show that 3,5-dihydroxyphenylglycine triggers the phosphorylation and activation of protein tyrosine kinase 2-β (PTK2B, also referred to as Pyk2) and of calcium/calmodulin-dependent protein kinase II in wild-type brain slices but not in Alzheimer disease transgenic brain slices or wild-type slices incubated with Aβo. This study further distinguishes two sep. Aβo-dependent signaling cascades, one dependent on extracellular Ca2+ and Fyn kinase activation and the other dependent on the release of Ca2+ from intracellular stores. Thus, Aβo triggers multiple distinct PrPC-mGluR5-dependent events implicated in neurodegeneration and dementia. We propose that targeting the PrPC-mGluR5 complex will reverse aberrant Aβo-triggered states of the complex to allow physiol. fluctuations of glutamate signaling.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslaktL3P&md5=b338b288603f6edc0d4b6ed1f615df82
    55. 55
      Abedini, A., Cao, P., Plesner, A., Zhang, J., He, M., Derk, J., Patil, S. A., Rosario, R., Lonier, J., Song, F. (2018) RAGE Binds Preamyloid IAPP Intermediates and Mediates Pancreatic β Cell Proteotoxicity. J. Clin. Invest. 128 (2), 682– 698,  DOI: 10.1172/JCI85210
      55
      RAGE binds preamyloid IAPP intermediates and mediates pancreatic β cell proteotoxicity
      Abedini Andisheh; Zhang Jinghua; He Meilun; Derk Julia; Patil Sachi A; Rosario Rosa; Lonier Jacqueline; Song Fei; Schmidt Ann Marie; Cao Ping; Raleigh Daniel P; Plesner Annette; Koh Hyunwook; Li Huilin
      The Journal of clinical investigation (2018), 128 (2), 682-698 ISSN:.
      Islet amyloidosis is characterized by the aberrant accumulation of islet amyloid polypeptide (IAPP) in pancreatic islets, resulting in β cell toxicity, which exacerbates type 2 diabetes and islet transplant failure. It is not fully clear how IAPP induces cellular stress or how IAPP-induced toxicity can be prevented or treated. We recently defined the properties of toxic IAPP species. Here, we have identified a receptor-mediated mechanism of islet amyloidosis-induced proteotoxicity. In human diabetic pancreas and in cellular and mouse models of islet amyloidosis, increased expression of the receptor for advanced glycation endproducts (RAGE) correlated with human IAPP-induced (h-IAPP-induced) β cell and islet inflammation, toxicity, and apoptosis. RAGE selectively bound toxic intermediates, but not nontoxic forms of h-IAPP, including amyloid fibrils. The isolated extracellular ligand-binding domains of soluble RAGE (sRAGE) blocked both h-IAPP toxicity and amyloid formation. Inhibition of the interaction between h-IAPP and RAGE by sRAGE, RAGE-blocking antibodies, or genetic RAGE deletion protected pancreatic islets, β cells, and smooth muscle cells from h-IAPP-induced inflammation and metabolic dysfunction. sRAGE-treated h-IAPP Tg mice were protected from amyloid deposition, loss of β cell area, β cell inflammation, stress, apoptosis, and glucose intolerance. These findings establish RAGE as a mediator of IAPP-induced toxicity and suggest that targeting the IAPP/RAGE axis is a potential strategy to mitigate this source of β cell dysfunction in metabolic disease.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MvhtVKntA%253D%253D&md5=e8bdc41817d48f49d22e4f4b3695b129
    56. 56
      Vogl, T., Leukert, N., Barczyk, K., Strupat, K., and Roth, J. (2006) Biophysical Characterization of S100A8 and S100A9 in the Absence and Presence of Bivalent Cations. Biochim. Biophys. Acta, Mol. Cell Res. 1763 (11), 1298– 1306,  DOI: 10.1016/j.bbamcr.2006.08.028
      56
      Biophysical characterization of S100A8 and S100A9 in the absence and presence of bivalent cations
      Vogl, Thomas; Leukert, Nadja; Barczyk, Katarzyna; Strupat, Kerstin; Roth, Johannes
      Biochimica et Biophysica Acta, Molecular Cell Research (2006), 1763 (11), 1298-1306CODEN: BBAMCO; ISSN:0167-4889. (Elsevier Ltd.)
      S100A8 and S100A9 are two proinflammatory mols. belonging to the S100 family of calcium-binding proteins. Common to all S100 proteins, S100A8 and S100A9 form non-covalently assocd. complexes which have been shown to exhibit different functional properties. Besides dimerization, recent research is focused on the importance of higher oligomeric structures of S100 proteins induced by bivalent cations. While S100A8/S100A9-heterodimers are formed in the absence of calcium, tetramerization is strictly calcium-dependent. Heterodimer formation is not a simple process and our biophys. analyses (FRET, ESI-MS) demonstrate that simply mixing both subunits is not sufficient to induce complex formation. Steps of denaturation/renaturation are necessary for the recombinant complex to show identical biophys. properties as S100A8/S100A9 obtained from granulocytes. In addn. to calcium, both proteins are able to bind zinc with high affinity. Here, we demonstrate for the first time by different biophys. methods (MALDI-MS, ESI-MS, fluorescence spectroscopy) that zinc-binding, like calcium, induces (S100A8/S100A9)2-tetramers. Using mass spectrometric investigations, we demonstrate that zinc triggers the formation of (S100A8/S100A9)2-tetramers by zinc-specific binding sites rather than by interactions with calcium-specific EF-hands. The zinc-induced tetramer is structurally very similar to the calcium-induced tetramer. Thus, like calcium, zinc acts as a regulatory factor in S100A8/S100A9-dependent signaling pathways.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xht1CnsLbK&md5=f4bc53c5e2577488e442d1034458f067
    57. 57
      Wang, C., Iashchishyn, I. A., Kara, J., Foderà, V., Vetri, V., Sancataldo, G., Marklund, M., and Morozova-Roche, L. A. (2019) Proinflammatory and Amyloidogenic S100A9 Induced by Traumatic Brain Injury in Mouse Model. Neurosci. Lett. 699, 199– 205,  DOI: 10.1016/j.neulet.2019.02.012
      57
      Proinflammatory and amyloidogenic S100A9 induced by traumatic brain injury in mouse model
      Wang, Chao; Iashchishyn, Igor A.; Kara, John; Fodera, Vito; Vetri, Valeria; Sancataldo, Giuseppe; Marklund, Niklas; Morozova-Roche, Ludmilla A.
      Neuroscience Letters (2019), 699 (), 199-205CODEN: NELED5; ISSN:0304-3940. (Elsevier Ireland Ltd.)
      Traumatic brain injury (TBI) represents a significant risk factor for development of neurodegenerative diseases such as Alzheimer's and Parkinson's. The S100A9-driven amyloid-neuroinflammatory cascade occurring during primary and secondary TBI events can serve as a mechanistic link between TBI and Alzheimer's as demonstrated recently in the human brain tissues. Here by using immunohistochem. in the controlled cortical impact TBI mouse model we have found pro-inflammatory S100A9 in the brain tissues of all mice on the first and third post-TBI days, while 70% of mice did not show any S100A9 presence on seventh post-TBI day similar to controls. This indicates that defensive mechanisms effectively cleared S100A9 in these mouse brain tissues during post-TBI recovery. By using sequential immunohistochem. we have shown that S100A9 was produced by both neuronal and microglial cells. However, Aβ peptide deposits characteristic for Alzheimer's disease were not detected in any post-TBI animals. On the first and third post-TBI days S100A9 was found to aggregate intracellularly into amyloid oligomers, similar to what was previously obsd. in human TBI tissues. Complementary, by using Rayleigh scatting, intrinsic fluorescence and at. force microscopy we demonstrated that in vitro S100A9 self-assembles into amyloid oligomers within minutes. Its amyloid aggregation is highly dependent on changes of environmental conditions such as variation of calcium levels, pH, temp. and redn./oxidn., which might be relevant to perturbation of cellular and tissues homeostasis under TBI. Present results demonstrate that S100A9 induction mechanisms in TBI are similar in mice and humans, emphasizing that S100A9 is an important marker of brain injury and therefore can be a potential therapeutic target.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXjtFOkurY%253D&md5=00ce57ce6592952a11a2f6a928d0cd73
    58. 58
      Kayed, R., Canto, I., Breydo, L., Rasool, S., Lukacsovich, T., Wu, J., Albay, R., Pensalfini, A., Yeung, S., Head, E. (2010) Conformation Dependent Monoclonal Antibodies Distinguish Different Replicating Strains or Conformers of Prefibrillar Aβ Oligomers. Mol. Neurodegener. 5 (1), 57,  DOI: 10.1186/1750-1326-5-57
      58
      Conformation dependent monoclonal antibodies distinguish different replicating strains or conformers of prefibrillar Aβ oligomers
      Kayed, Rakez; Canto, Isabel; Breydo, Leonid; Rasool, Suhail; Lukacsovich, Tamas; Wu, Jessica; Albay, Ricardo, III; Pensalfini, Anna; Yeung, Stephen; Head, Elizabeth; Marsh, J. Lawrence; Glabe, Charles
      Molecular Neurodegeneration (2010), 5 (), 57CODEN: MNOEAZ; ISSN:1750-1326. (BioMed Central Ltd.)
      Background: Age-related neurodegenerative diseases share a no. of important pathol. features, such as accumulation of misfolded proteins as amyloid oligomers and fibrils. Recent evidence suggests that sol. amyloid oligomers and not the insol. amyloid fibrils may represent the primary pathol. species of protein aggregates. Results: We have produced several monoclonal antibodies that specifically recognize prefibrillar oligomers and do not recognize amyloid fibrils, monomer or natively folded proteins. Like the polyclonal antisera, the individual monoclonals recognize generic epitopes that do not depend on a specific linear amino acid sequence, but they display distinct preferences for different subsets of prefibrillar oligomers. Immunol. anal. of a no. of different prefibrillar Aβ oligomer prepns. show that structural polymorphisms exist in Aβ prefibrillar oligomers that can be distinguished on the basis of their reactivity with monoclonal antibodies. Western blot anal. demonstrates that the conformers defined by the monoclonal antibodies have distinct size distributions, indicating that oligomer structure varies with size. The different conformational types of Aβ prefibrillar oligomers can serve as they serve as templates for monomer addn., indicating that they seed the conversion of Aβ monomer into more prefibrillar oligomers of the same type. Conclusions: These results indicate that distinct structural variants or conformers of prefibrillar Aβ oligomers exist that are capable of seeding their own replication. These conformers may be analogous to different strains of prions.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhs1ams7fE&md5=54b7c4aca24f41e66a682f2a78efc8e0
    59. 59
      Eilers, P. H. C. (2003) A Perfect Smoother. Anal. Chem. 75 (14), 3631– 3636,  DOI: 10.1021/ac034173t
      59
      A Perfect Smoother
      Eilers, Paul H. C.
      Analytical Chemistry (2003), 75 (14), 3631-3636CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      The A. Savitzky and M. Golay (1964) filter has several disadvantages. A very attractive alternative is a smoother based on penalized least squares, extending ideas presented by E. T. Whittaker (1923). This smoother is extremely fast, gives continuous control over smoothness, interpolates automatically, and allows fast leave-one-out cross-validation. It can be programmed in a few lines of Matlab code. Theory, implementation, and applications are presented.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXktFGqsLw%253D&md5=eba4aed2ebbf3e48bd80049d8e0ce165
    60. 60
      Wasylewski, Z., Koloczek, H., and Wasniowska, A. (1988) Fluorescence-Quenching-Resolved Spectroscopy of Proteins. Eur. J. Biochem. 172 (3), 719– 724,  DOI: 10.1111/j.1432-1033.1988.tb13948.x
      60
      Fluorescence-quenching-resolved spectroscopy of proteins
      Wasylewski, Zygmunt; Koloczek, Henryk; Wasniowska, Alicja
      European Journal of Biochemistry (1988), 172 (3), 719-24CODEN: EJBCAI; ISSN:0014-2956.
      A new procedure is described for using fluorescence-quenching data of tryptophan residues in proteins to resolve their fluorescence emission spectra. In this concept, the Stern-Volmer quenching plot is detd. at each particular emission wavelength and iterative nonlinear least-squares fitting procedure allowed to resolve the steady-state emission spectra into components. The resolved components, attributed to each of tryptophan residue, can be characterized by different accessibility to the quencher. The ability to resolve fluorescence emission spectra can be improved by using different kinds of efficient quenchers, which can selectively quench the emission of exposed or both exposed and buried fluorophores. The method was used to decomp. emission fluorescence spectra in 2-tryptophan-contg. proteins: horse liver dehydrogenase, sperm whale apomyoglobin, and metalloprotease from Staphylococcus aureus. The resolved spectra of alc. dehydrogenase and metalloprotease are in excellent agreement with those previously obtained by single-photon counting or phase methods. The method presented here is tech. simple and does not require expensive instrumentation.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1cXhsVKmt70%253D&md5=bb0cf515871a8a98d9b958cd066dde9e
    61. 61
      Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C., and Ferrin, T. E. (2004) UCSF Chimera-AVisualization Sytem for Exploratory Research and Analysis Vesrion. J. Comput. Chem. 25, 1605– 1612,  DOI: 10.1002/jcc.20084
      61
      UCSF Chimera-A visualization system for exploratory research and analysis
      Pettersen, Eric F.; Goddard, Thomas D.; Huang, Conrad C.; Couch, Gregory S.; Greenblatt, Daniel M.; Meng, Elaine C.; Ferrin, Thomas E.
      Journal of Computational Chemistry (2004), 25 (13), 1605-1612CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)
      The design, implementation, and capabilities of an extensible visualization system, UCSF Chimera, are discussed. Chimera is segmented into a core that provides basic services and visualization, and extensions that provide most higher level functionality. This architecture ensures that the extension mechanism satisfies the demands of outside developers who wish to incorporate new features. Two unusual extensions are presented: Multiscale, which adds the ability to visualize large-scale mol. assemblies such as viral coats, and Collab., which allows researchers to share a Chimera session interactively despite being at sep. locales. Other extensions include Multalign Viewer, for showing multiple sequence alignments and assocd. structures; ViewDock, for screening docked ligand orientations; Movie, for replaying mol. dynamics trajectories; and Vol. Viewer, for display and anal. of volumetric data. A discussion of the usage of Chimera in real-world situations is given, along with anticipated future directions. Chimera includes full user documentation, is free to academic and nonprofit users, and is available for Microsoft Windows, Linux, Apple Mac OS X, SGI IRIX, and HP Tru64 Unix from http://www.cgl.ucsf.edu/chimera/.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXmvVOhsbs%253D&md5=944b175f440c1ff323705987cf937ee7
    62. 62
      Miletić, V., Odorčić, I., Nikolić, P., and Svedružić, Ž. M. (2017) In Silico Design of the First DNA-Independent Mechanism-Based Inhibitor of Mammalian DNA Methyltransferase Dnmt1. PLoS One 12, e0174410  DOI: 10.1371/journal.pone.0174410
      62
      In silico design of the first DNA-independent mechanism-based inhibitor of mammalian DNA methyltransferase Dnmt1
      Miletic, Vedran; Odorcic, Ivica; Nikolic, Patrik; Svedruzic, Zeljko M.
      PLoS One (2017), 12 (4), e0174410/1-e0174410/21CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
      We use our earlier exptl. studies of the catalytic mechanism of DNA methyltransferases to prep. in silico a family of novel mechanism-based inhibitors of human Dnmt1. Highly specific inhibitors of DNA methylation can be used for anal. of human epigenome and for the creation of iPS cells. We describe a set of adenosyl-1-methyl-pyrimidin-2-one derivs. as novel mechanism based inhibitors of mammalian DNA methyltransferase Dnmt1. The inhibitors have been designed to bind simultaneously in the active site and the cofactor site and thus act as transition- state analogs. Mol. dynamics studies showed that the lead compd. can form between 6 to 9 binding interactions with Dnmt1. QM/MM anal. showed that the upon binding to Dnmt1 the inhibitor can form a covalent adduct with active site Cys1226 and thus act as a mechanism-based suicide-inhibitor. The inhibitor can target DNA-bond and DNAfree form of Dnmt1, however the suicide-inhibition step is more likely to happen when DNA is bound to Dnmt1. The validity of presented anal. is described in detail using 69 modifications in the lead compd. structure. In total 18 of the presented 69 modifications can be used to prep. a family of highly specific inhibitors that can differentiate even between closely related enzymes such as Dnmt1 and Dnmt3a DNA methyltransferases. Presented results can be used for prepn. of some highly specific and potent inhibitors of mammalian DNA methylation with specific pharmacol. properties.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsValsrbL&md5=e52a25b05645fb00f338b89d0193afa6
    63. 63
      Ruiz-Carmona, S., Alvarez-Garcia, D., Foloppe, N., Garmendia-Doval, A. B., Juhos, S., Schmidtke, P., Barril, X., Hubbard, R. E., and Morley, S. D. (2014) rDock: a Fast, Versatile and Open Source Program for Docking Ligands to Proteins and Nucleic Acids. PLoS Comput. Biol. 10, e1003571  DOI: 10.1371/journal.pcbi.1003571
      63
      rDock: a fast, versatile and open source program for docking ligands to proteins and nucleic acids
      Ruiz-Carmona, Sergio; Alvarez-Garcia, Daniel; Foloppe, Nicolas; Garmendia-Doval, A. Beatriz; Juhos, Szilveszter; Schmidtke, Peter; Barril, Xavier; Hubbard, Roderick E.; Morley, S. David
      PLoS Computational Biology (2014), 10 (4), e1003571/1-e1003571/7, 7 pp.CODEN: PCBLBG; ISSN:1553-7358. (Public Library of Science)
      Identification of chem. compds. with specific biol. activities is an important step in both chem. biol. and drug discovery. When the structure of the intended target is available, one approach is to use mol. docking programs to assess the chem. complementarity of small mols. with the target; such calcns. provide a qual. measure of affinity that can be used in virtual screening (VS) to rank order a list of compds. according to their potential to be active. rDock is a mol. docking program developed at Vernalis for high-throughput VS (HTVS) applications. Evolved from RiboDock, the program can be used against proteins and nucleic acids, is designed to be computationally very efficient and allows the user to incorporate addnl. constraints and information as a bias to guide docking. This article provides an overview of the program structure and features and compares rDock to two ref. programs, AutoDock Vina (open source) and Schrodinger's Glide (com.). In terms of computational speed for VS, rDock is faster than Vina and comparable to Glide. For binding mode prediction, rDock and Vina are superior to Glide. The VS performance of rDock is significantly better than Vina, but inferior to Glide for most systems unless pharmacophore constraints are used; in that case rDock and Glide are of equal performance. The program is released under the Lesser General Public License and is freely available for download, together with the manuals, example files and the complete test sets, at online.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsVGlsL%252FO&md5=e4cb786d6567fdc7f2a46f64955a9992
    64. 64
      Lee, J., Patel, D. S., Ståhle, J., Park, S. J., Kern, N. R., Kim, S., Lee, J., Cheng, X., Valvano, M. A., Holst, O. (2019) CHARMM-GUI Membrane Builder for Complex Biological Membrane Simulations with Glycolipids and Lipoglycans. J. Chem. Theory Comput. 15, 775– 786,  DOI: 10.1021/acs.jctc.8b01066
      64
      CHARMM-GUI Membrane Builder for Complex Biological Membrane Simulations with Glycolipids and Lipoglycans
      Lee, Jumin; Patel, Dhilon S.; Stahle, Jonas; Park, Sang-Jun; Kern, Nathan R.; Kim, Seonghoon; Lee, Joonseong; Cheng, Xi; Valvano, Miguel A.; Holst, Otto; Knirel, Yuriy A.; Qi, Yifei; Jo, Sunhwan; Klauda, Jeffery B.; Widmalm, Goran; Im, Wonpil
      Journal of Chemical Theory and Computation (2019), 15 (1), 775-786CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)
      Glycolipids (such as glycoglycerolipids, glycosphingolipids, and glycosylphosphatidylinositol) and lipoglycans (such as lipopolysaccharides (LPS), lipooligosaccharides (LOS), mycobacterial lipoarabinomannan, and mycoplasma lipoglycans) are typically found on the surface of cell membranes and play crucial roles in various cellular functions. Characterizing their structure and dynamics at the mol. level is essential to understand their biol. roles, but systematic generation of glycolipid and lipoglycan structures is challenging because of great variations in lipid structures and glycan sequences (i.e., carbohydrate types and their linkages). To facilitate the generation of all-atom glycolipid/LPS/LOS structures, we have developed Glycolipid Modeler and LPS Modeler in CHARMM-GUI (http://www.charmm-gui.org), a web-based interface that simplifies building of complex biol. simulation systems. In addn., we have incorporated these modules into Membrane Builder so that users can readily build a complex sym. or asym. biol. membrane system with various glycolipids and LPS/LOS. These tools are expected to be useful in innovative and novel glycolipid/LPS/LOS modeling and simulation research by easing tedious and intricate steps in modeling complex biol. systems and shall provide insight into structures, dynamics, and underlying mechanisms of complex glycolipid-/LPS-/LOS-contg. biol. membrane systems.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisVOitrbO&md5=a212a0bfce1818bc74f2b317eff3af93
    65. 65
      Sousa da Silva, A. W and Vranken, W. F (2012) ACPYPE-Antechamber Python Parser Interface. BMC Res. Notes 5, 367,  DOI: 10.1186/1756-0500-5-367
      65
      ACPYPE - AnteChamber PYthon Parser interfacE
      Sousa da Silva Alan W; Vranken Wim F
      BMC research notes (2012), 5 (), 367 ISSN:.
      BACKGROUND: ACPYPE (or AnteChamber PYthon Parser interfacE) is a wrapper script around the ANTECHAMBER software that simplifies the generation of small molecule topologies and parameters for a variety of molecular dynamics programmes like GROMACS, CHARMM and CNS. It is written in the Python programming language and was developed as a tool for interfacing with other Python based applications such as the CCPN software suite (for NMR data analysis) and ARIA (for structure calculations from NMR data). ACPYPE is open source code, under GNU GPL v3, and is available as a stand-alone application at http://www.ccpn.ac.uk/acpype and as a web portal application at http://webapps.ccpn.ac.uk/acpype. FINDINGS: We verified the topologies generated by ACPYPE in three ways: by comparing with default AMBER topologies for standard amino acids; by generating and verifying topologies for a large set of ligands from the PDB; and by recalculating the structures for 5 protein-ligand complexes from the PDB. CONCLUSIONS: ACPYPE is a tool that simplifies the automatic generation of topology and parameters in different formats for different molecular mechanics programmes, including calculation of partial charges, while being object oriented for integration with other applications.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38fitlWjtg%253D%253D&md5=60f750ba98c975374b351a39a1fa0ec4
    66. 66
      Kim, S., Lee, J., Jo, S., Brooks, C. L., 3rd, Lee, H. S., and Im, W. (2017) CHARMM-GUI Ligand Reader and Modeler for CHARMM Force Field Generation of Small Molecules. J. Comput. Chem. 38, 1879– 1886,  DOI: 10.1002/jcc.24829
      66
      CHARMM-GUI ligand reader and modeler for CHARMM force field generation of small molecules
      Kim, Seonghoon; Lee, Jumin; Jo, Sunhwan; Brooks, Charles L., III; Lee, Hui Sun; Im, Wonpil
      Journal of Computational Chemistry (2017), 38 (21), 1879-1886CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)
      Reading ligand structures into any simulation program is often nontrivial and time consuming, esp. when the force field parameters and/or structure files of the corresponding mols. are not available. To address this problem, we have developed Ligand Reader & Modeler in CHARMM-GUI. Users can upload ligand structure information in various forms (using PDB ID, ligand ID, SMILES, MOL/MOL2/SDF file, or PDB/mmCIF file), and the uploaded structure is displayed on a sketchpad for verification and further modification. Based on the displayed structure, Ligand Reader & Modeler generates the ligand force field parameters and necessary structure files by searching for the ligand in the CHARMM force field library or using the CHARMM general force field (CGenFF). In addn., users can define chem. substitution sites and draw substituents in each site on the sketchpad to generate a set of combinatorial structure files and corresponding force field parameters for throughput or alchem. free energy simulations. Finally, the output from Ligand Reader & Modeler can be used in other CHARMM-GUI modules to build a protein-ligand simulation system for all supported simulation programs, such as CHARMM, NAMD, GROMACS, AMBER, GENESIS, LAMMPS, Desmond, OpenMM, and CHARMM/OpenMM. Ligand Reader & Modeler is available as a functional module of CHARMM-GUI at http://www.charmm-gui.org/input/ligandrm.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnslKhtLk%253D&md5=3e872e011783f98bc14594d91bc142ef
    67. 67
      Van Der Spoel, D., Lindahl, E., Hess, B., Groenhof, G., Mark, A. E., and Berendsen, H. J. (2005) GROMACS: Fast, Flexible, and Free. J. Comput. Chem. 26, 1701– 1718,  DOI: 10.1002/jcc.20291
      67
      GROMACS: Fast, flexible, and free
      Van Der Spoel, David; Lindahl, Erik; Hess, Berk; Groenhof, Gerrit; Mark, Alan E.; Berendsen, Herman J. C.
      Journal of Computational Chemistry (2005), 26 (16), 1701-1718CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)
      This article describes the software suite GROMACS (Groningen MAchine for Chem. Simulation) that was developed at the University of Groningen, The Netherlands, in the early 1990s. The software, written in ANSI C, originates from a parallel hardware project, and is well suited for parallelization on processor clusters. By careful optimization of neighbor searching and of inner loop performance, GROMACS is a very fast program for mol. dynamics simulation. It does not have a force field of its own, but is compatible with GROMOS, OPLS, AMBER, and ENCAD force fields. In addn., it can handle polarizable shell models and flexible constraints. The program is versatile, as force routines can be added by the user, tabulated functions can be specified, and analyses can be easily customized. Nonequil. dynamics and free energy detns. are incorporated. Interfaces with popular quantum-chem. packages (MOPAC, GAMES-UK, GAUSSIAN) are provided to perform mixed MM/QM simulations. The package includes about 100 utility and anal. programs. GROMACS is in the public domain and distributed (with source code and documentation) under the GNU General Public License. It is maintained by a group of developers from the Universities of Groningen, Uppsala, and Stockholm, and the Max Planck Institute for Polymer Research in Mainz. Its Web site is http://www.gromacs.org.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXht1SlsbbO&md5=4aa71b1dc0b5b4978a88b0568245a265
    68. 68
      Cheung, Y. T., Lau, W. K., Yu, M. S., Lai, C. S., Yeung, S. C., So, K. F., and Chang, R. C. (2009) Effects of All-Trans-Retinoic Acid on Human SH-SY5Y Neuroblastoma as In Vitro Model in Neurotoxicity Research. NeuroToxicology 30 (1), 127– 135,  DOI: 10.1016/j.neuro.2008.11.001
      68
      Effects of all-trans-retinoic acid on human SH-SY5Y neuroblastoma as in vitro model in neurotoxicity research
      Cheung, Yuen-Ting; Lau, Way Kwok-Wai; Yu, Man-Shan; Lai, Cora Sau-Wan; Yeung, Sze-Chun; So, Kwok-Fai; Chang, Raymond Chuen-Chung
      NeuroToxicology (2009), 30 (1), 127-135CODEN: NRTXDN; ISSN:0161-813X. (Elsevier B.V.)
      Human neuroblastoma SH-SY5Y is a dopaminergic neuronal cell line which has been used as an in vitro model for neurotoxicity expts. Although the neuroblastoma is usually differentiated by all-trans-retinoic acid (RA), both RA-differentiated and undifferentiated SH-SY5Y cells have been used in neuroscience research. However, the changes in neuronal properties triggered by RA as well as the subsequent responsiveness to neurotoxins have not been comprehensively studied. Therefore, we aim to re-evaluate the differentiation property of RA on this cell line. We hypothesize that modulation of signaling pathways and neuronal properties during RA-mediated differentiation in SH-SY5Y cells can affect their susceptibility to neurotoxins. The differentiation property of RA was confirmed by showing an extensive outgrowth of neurites, increased expressions of neuronal nuclei, neuron specific enolase, synaptophysin and synaptic assocd. protein-97, and decreased expression of inhibitor of differentiation-1. While undifferentiated SH-SY5Y cells were susceptible to 6-OHDA and MPP+, RA-differentiation conferred SH-SY5Y cells higher tolerance, potentially by up-regulating survival signaling, including Akt pathway as inhibition of Akt removed RA-induced neuroprotection against 6-OHDA. As a result, the real toxicity cannot be revealed in RA-differentiated cells. Therefore, undifferentiated SH-SY5Y is more appropriate for studying neurotoxicity or neuroprotection in exptl. Parkinson's disease research.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtFeqsbw%253D&md5=c0fd9e12f367cc8258ce304212571828
    69. 69
      Nosi, D., Mercatelli, R., Chellini, F., Soria, S., Pini, A., Formigli, L., and Quercioli, F. (2013) A Molecular Imaging Analysis of Cx43 Association with Cdo During Skeletal Myoblast Differentiation. J. Biophotonics 6 (8), 612– 621,  DOI: 10.1002/jbio.201200063
      69
      A molecular imaging analysis of Cx43 association with Cdo during skeletal myoblast differentiation
      Nosi, Daniele; Mercatelli, Raffaella; Chellini, Flaminia; Soria, Silvia; Pini, Alessandro; Formigli, Lucia; Quercioli, Franco
      Journal of Biophotonics (2013), 6 (8), 612-621CODEN: JBOIBX; ISSN:1864-063X. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Cell-to-cell contacts are crucial for cell differentiation. The promyogenic cell surface protein, Cdo, functions as a component of multiprotein clusters to mediate cell adhesion signaling. Connexin 43, the main connexin forming gap junctions, also plays a key role in myogenesis. At least part of its effects is independent of the intercellular channel function, but the mechanisms underlying are unknown. Here, using multiple optical approaches, we provided the first evidence that Cx43 phys. interacts with Cdo to form dynamic complexes during myoblast differentiation, offering clues for considering this interaction a structural basis of the channel-independent function of Cx43.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1amu77P&md5=cd23bd3959355f60143523005ad14929

  • Supporting Information

    Supporting Information

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acschemneuro.0c00828.

    • Time dependences of ThT fluorescence during OleA incubation; interaction of S100A9 amyloids with A11 amyloid oligomer specific antibodies upon increasing OleA concentration; cell viability and intracellular free Ca2+ level in SH-SY5Y cells affected by S100A9 amyloids; preformed S100A9 fibrils treated with OleA during various times; cytotoxicity of S100A9 fibrils to undifferentiated and differentiated SH-SY5Y cells (PDF)


    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.