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CommunicationMarch 26, 2020

Copper Transporters? Glutathione Reactivity of Products of Cu–Aβ Digestion by Neprilysin
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Ewelina Stefaniak
Ewelina Stefaniak
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawińskiego 5a, 02-106 Warsaw, Poland
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Dawid Płonka
Dawid Płonka
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawińskiego 5a, 02-106 Warsaw, Poland
More by Dawid Płonka
http://orcid.org/0000-0002-4076-9231
Paulina Szczerba
Paulina Szczerba
Chair of Medical Biotechnology, Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland
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Nina E. Wezynfeld
Nina E. Wezynfeld
Chair of Medical Biotechnology, Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland
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Wojciech Bal*
Wojciech Bal
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawińskiego 5a, 02-106 Warsaw, Poland
*E-mail [email protected]
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http://orcid.org/0000-0003-3780-083X

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Inorganic Chemistry

Cite this: Inorg. Chem. 2020, 59, 7, 4186–4190

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https://doi.org/10.1021/acs.inorgchem.0c00427

Published March 26, 2020

Abstract

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Aβ_4–42 is the major subspecies of Aβ peptides characterized by avid Cu(II) binding via the ATCUN/NTS motif. It is thought to be produced in vivo proteolytically by neprilysin, but in vitro experiments in the presence of Cu(II) ions indicated preferable formation of C-terminally truncated ATCUN/NTS species including Cu^IIAβ_4–16, Cu^IIAβ_4–9, and also Cu^IIAβ_12–16, all with nearly femtomolar affinities at neutral pH. Such small complexes may serve as shuttles for copper clearance from extracellular brain spaces, on condition they could survive intracellular conditions upon crossing biological barriers. In order to ascertain such possibility, we studied the reactions of Cu^IIAβ_4–16, Cu^IIAβ_4–9, Cu^IIAβ_12–16, and Cu^IIAβ_1–16 with reduced glutathione (GSH) under aerobic and anaerobic conditions using absorption spectroscopy and mass spectrometry. We found Cu^IIAβ_4–16 and Cu^IIAβ_4–9 to be strongly resistant to reduction and concomitant formation of Cu(I)–GSH complexes, with reaction times ∼10 h, while Cu^IIAβ_12–16 was reduced within minutes and Cu^IIAβ_1–16 within seconds of incubation. Upon GSH exhaustion by molecular oxygen, the Cu^IIAβ complexes were reformed with no concomitant oxidative damage to peptides. These finding reinforce the concept of Aβ_4–x peptides as physiological trafficking partners of brain copper.

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Synopsis

Aβ₄₋₁₆, Aβ₄₋₉, and Aβ₁₂₋₁₆, oligopeptide products of β-amyloid degradation by neprilysin, bind Cu^II ions very tightly and are considered as possible Cu^II carriers in the brain. We demonstrated that Cu^II(Aβ_4−x) complexes, but not Cu^II(Aβ₁₂₋₁₆), are kinetically resistant to reduction by glutathione. No covalent Aβ peptide modifications were observed during the copper reduction and reoxidation by ambient oxygen, yielding the original complexes. These features suggest that Cu^II(Aβ_4−x) complexes might be able to cross the blood−brain barrier.

Aβ peptides are products of extracellular hydrolysis of amyloid precursor protein (APP) present in neuronal synaptic membranes. (1−3) Overproduction or excessive aggregation of Aβ has been long implicated as an upstream cause of neuronal death in Alzheimer’s disease (AD). (4,5) This concept gained recent reinforcement when direct deleterious action of Aβ dimers on neuronal glutamate receptors was demonstrated. (6) Aβ peptides are a heterogeneous peptide family, generated by a number of primary (acting on APP) and secondary (acting on Aβ) proteases. The most studied members of the Aβ family are Aβ_1–40 and Aβ_1–42, but current analytical studies demonstrated a high abundance of the N-truncated Aβ_4–42 peptide in both healthy and AD human brains. (7,8)

Aβ_1–x peptides (x denotes naturally occurring 42 and 40 species, as well as model peptides 28 and 16) bind a Cu^II ion avidly with K_d about 100 pM. The resulting complexes can be easily activated by ascorbate to catalyze the production of reactive oxygen species (ROS). (9−12) Supported by reports on deranged copper metabolism in AD brains and colocalization of copper and aggregated Aβ peptides in amyloid plaques, these properties gave rise to a concept of Cu^II–Aβ_1–x complexes as neurotoxic species in AD. (5,13,14)

Remarkably, Aβ_4–42 and its C-terminally truncated analogs are Cu^II chelators much more avid (3000 times at pH 7.4 for Aβ_4–16 vs Aβ_1–16) and specific than Aβ_1–x peptides. (15) This results from a specific character of their N-terminal sequence, Phe-Arg-His, belonging to the ATCUN/NTS family. (16) Furthermore, unlike Cu^II–Aβ_1–x complexes, Cu^II–Aβ_4–x did not generate ROS and could not be reduced electrochemically to Cu^I species. (15) These findings suggest that Aβ_4–42 might actually serve as synaptic copper scavenger, helping restore the resting state of glutamatergic synapse, after the physiological Cu²⁺ release during neurotransmission. (17,18)

Digestion of Aβ peptides is considered as one of the major routes of their detoxification. They are thought to be cleaved down to oligopeptides that can cross the blood–brain barrier. (19,20) An Aβ-specific peptidase has not been found. Instead, a number of brain proteases with other known functions have been implicated in this process, including neprilysin (NEP), angiotensinogen converting enzyme (ACE), and insulin degrading enzyme (IDE). (21) NEP action on Aβ_1–x has also been indicated as the main source of Aβ_4–x in the brain. (22,23) A recent study of Aβ_1–16 and Aβ_1–40 cleavage by NEP in the presence and absence of Cu^II ions did not quite reproduce such activity, however. Instead a significant extent of peptide fragmentation was observed. The fast digestion of the Gly9–Tyr10 bond yielded the Cu^II-complexed short peptide Aβ_4–9. Additionally, a complex of Aβ_12–16 was generated abundantly when Aβ_1–16 was used as a substrate and was also present as a minor species for Aβ_1–40. (24) Aβ_4–9 and Aβ_12–16 are even stronger Cu^II chelators than Aβ_4–16, with K_d of 6.6 fM and 9.5 fM vs 30 fM at pH 7.4. (25) This finding gave rise to an idea that such complexes might serve as shuttles for removing excess copper from the brain.

Crossing the blood–brain barrier (BBB) is a complicated and not fully elucidated process, involving passage through the layer of epithelial cells forming the blood vessel walls. (26) Therefore, the transferred molecule could be exposed for a certain amount of time to intracellular conditions, including millimolar (0.5–10 mM) concentrations of reduced glutathione (GSH). (27) GSH is the main reducing agent for Cu^II species entering the cell interior and is also implicated in the intracellular Cu^I transport. (28−30) It is also present extracellularly in the brain, serving as neuromodulator. (31) GSH facilitated the otherwise very sluggish reductive copper transfer from Aβ_4–16 to metallothionein-3 (MT-3), indicating that it could reduce the Aβ_4–x-bound Cu(II) to Cu(I) despite the electrochemical resistance of the parent complex to such reaction. (32)

We therefore decided to follow the reaction of Aβ_4–x peptides with GSH in more detail, using Aβ_4–16 as a suitable soluble, nonaggregating substitute of Aβ_4–42. We also tested Aβ_4–9 and Aβ_12–16. Our experiments were performed under aerobic (21% O₂) and anaerobic (<1% O₂) conditions in order to gain insight into the relation of the studied reaction to oxidative stress conditions. The differential kinetic resistance of the studied complexes to reduction supports their possible roles in Cu^II transport in the brain.

In initial experiments, 0.315 mM Cu²⁺ ions were reacted for 24 h with 1.75 mM GSH in 20 mM ammonium acetate at 25 °C under aerobic conditions, with and without 0.35 mM Aβ_4–16 (0.9/5/1 and 0.9/5 molar ratios, Figure 1A and Supporting Information Figure S1, respectively). In control experiments 1.75 mM glutathione disulfide (GSSG) was used instead of GSH (Figure S2), and Cu²⁺ ions were omitted from the reaction of GSH with Aβ_4–16 (Figure S3). These experiments allowed us to identify and assign the spectral changes occurring in the course of reactions of Cu^II(Aβ_4–16) with GSH. New bands in the near-UV range between 315 and 265 nm (Figure S4) appeared gradually in the presence of Aβ_4–16, at the expense of the Cu(II) band of the 4N complex at 525 nm. In the absence of the peptide, the same bands emerged rapidly. They could be assigned to the Cu(I) complex of GSH, reported previously by others. (33,34)

Figure 1. UV–vis spectra of the reaction of 0.315 mM Cu(II) ions with 1.75 mM GSH in the presence of 0.35 mM Aβ_4–16 in 20 mM ammonium acetate buffer, pH 7.4, carried out for 25–30 h at 25 °C under aerobic (A) and anaerobic (B) conditions. UV–vis spectrum of Cu(II)Aβ_4–16 showed by dashed line. The spectra were recorded in 10 min intervals. Insets show selected kinetic traces at 525 nm.

This Cu^II reduction phase lasted for about 9 h and reproducibly reached about 65% Cu^II conversion at 25 °C, as calculated from the intensity of the Cu^II(Aβ_4–16) d–d band at 525 nm (Table 1). It was followed by the shorter reoxidation phase, which led to a practically full restoration of Cu^II(Aβ_4–16). In the absence of Aβ_4–16, the Cu^IIGSSG complex absorbing at 625 nm was the final reaction product (Figure S1). It was not formed in the presence of Cu^II(Aβ_4–16), because of the log K difference at pH 7.4 in favor of the latter, 10.37 vs 13.53. (15,35) The reaction rates increased with temperature (Figure S5). The ESI-MS analysis of reaction products indicated the absence of covalent oxidative modification of Aβ_4–16 (Figures S6 and S7). The only change in its mass spectrum was due to partial detachment of bound Cu^II ion resulting from its capture by GSH. The mass deficit of 2 Da, seen only in the copper-containing species, indicated the native ATCUN/NTS complex with two deprotonated, Cu^II-bound amide nitrogens. (15) A transient spectral feature at 390–405 nm accompanied the Cu^I reoxidation phase. The same feature was present during the reoxidation phase of Cu^II/GSH reaction in the absence of Aβ_4–16 (Figure S8); hence it involves neither Aβ_4–16 nor its Cu^II complex. A similar band was seen previously in a study of Cu^I complexes in MT-3 and interpreted to originate from Cu^I–Cu^I interactions in the Cu₄-thiolate cluster. (36) Indeed, Cu^I preferentially forms a Cu₄GSH₆ cluster at the molar excess of GSH. (33) However, the selective appearance of this low-energy band during oxidative decomposition of Cu₄GSH₆ by molecular oxygen suggests a contribution from partially oxidized species such as disulfide or Cu^II. This issue will be investigated separately.

Table 1. Initial Reaction Velocities, V₀, and Conversion Degrees of Cu^II Reduction to Cu^I/GSH in the Presence of Aβ_4–16 Peptide^a

	aerobic			anaerobic
	18 °C	25 °C	37 °C	25 °C
V₀	5.0 ± 0.2	10 ± 1	21 ± 3	9 ± 4
conversion degree	0.58 ± 0.03	0.65 ± 0.04	0.64 ± 0.05	0.92 ± 0.03

^{^a}

Determined from the initial decay of the d–d band at 525 nm. Velocities are given in nM/s; all data are shown ± SD.

The next series of reduction experiments was performed under the effectively anaerobic conditions, and indeed only the reduction phase of the reaction was observed during the 24 h incubation, leading to full Cu^II reduction (Figure 1B). Upon extending the incubation to 50 h, however, the reoxidation phase was observed after about 36 h of the incubation (Figure S9). This effect was due to ambient oxygen penetration of the samples residing in the spectrophotometer. The comparison of kinetic traces indicated the similarity of the early phase of the reduction process between the aerobic and anaerobic conditions (Figure S10). These traces exhibited the mathematical form of first order kinetics for all conditions, only differing by the degree of Cu^II reduction: ca. 65% under aerobic and nearly 100% under anaerobic conditions. However, as the actual reaction order was not determined, we compared the kinetics of individual reactions using initial velocities. The rate of Cu(II) reduction did not depend on the presence of ambient oxygen (Tables 1 and 2).

Table 2. Initial Reaction Velocities, V₀, and Conversion Degrees of Cu^II Reduction to Cu^I/GSH Performed at 25 °C in the Presence of Aβ_4–9 and Aβ_12–16 Peptides^a

	aerobic	anaerobic
Aβ_4–9
V₀	7 ± 2	10 ± 2
conversion degree	0.54 ± 0.05	0.91 ± 0.04
Aβ_12–16
V₀	2200 ± 500	1600 ± 400
conversion degree	0.97 ± 0.02	0.98 ± 0.02

^{^a}

Determined from the initial decay of the d–d band (527 and 524 nm, respectively). Velocities are given in nM/s; all data are shown ± SD.

Figure 2 presents examples of experiments performed aerobically with Cu(II) complexes of Aβ_4–9 and Aβ_12–16 peptides. The CuAβ_4–9 reduction was similarly slow, but that of CuAβ_12–16 was about 200 times faster than that of CuAβ_4–16 (Table 2). The reoxidation phase occurred, however, similarly in all three cases (Figures 1 and 2). The reduction of CuAβ_1–16 under the same conditions was too fast for quantitation (Figure S11).

Figure 2. UV–vis spectra of the reaction of 0.315 mM Cu(II) ions with 1.75 mM GSH in the presence of 0.35 mM Aβ_4–9 (A) and Aβ_12–16 (B) in 20 mM ammonium acetate buffer, pH 7.4, carried out for 22–24 h at 25 °C under aerobic conditions. The spectra were recorded in 10 min intervals. Insets show selected kinetic traces at 527 nm (A) and 524 nm (B).

The kinetic, but not thermodynamic, resistance of Cu^IIAβ_4–16 to reduction to Cu^I species by thiols has been indicated in previous experiments. (32,37) Its kinetic character is reinforced by fast reduction of Cu^IIAβ_12–16, which has higher thermodynamic stability than Cu^IIAβ_4–16. (15,25) A clue for the mechanistic basis of this behavior is provided by the accelerating role of glutamic acid in both reductive copper transfer to MT-3 and nonreductive transfer to EDTA, along the affinity gradient. (38) This finding was interpreted in terms of assistance of copper transfer from the ATCUN/NTS motif via a putative partially coordinated intermediate species prone to form a ternary complex with a small transfer catalyst ligand. A similar mechanism was recently proposed in a study of Cu(II) reduction by GSH alone. (39) In the case of Cu^IIAβ_12–16, the fast Cu^II reduction is most likely facilitated by the His residue in position two of the peptide chain, able to provide an alternatively coordinated, minor 3N species. (40,41) Such complexes are known to exchange Cu^II ions rapidly. (42) They can also stabilize transient Cu^I species. (38) Cu^IIAβ_1–16 is known to facilitate Cu^II reduction to Cu^I by a number of mechanisms and is prone to ternary complex formation. (43,44)

Summarizing, the results presented above indicate that Cu^IIAβ_4–16 and especially Cu^IIAβ_4–9 are sufficiently kinetically resistant to reduction by physiological concentrations of GSH to survive in the cell cytosol for hours without eliciting oxidative damage, while Cu^IIAβ_12–16 and Cu^IIAβ_1–16 do not have this ability. Therefore, Cu^IIAβ_4–x complexes are good candidates to shuffle Cu^II across the blood–brain barrier and in and out of the brain cells.

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.inorgchem.0c00427.

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Author Information

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Corresponding Author
- Wojciech Bal - Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawińskiego 5a, 02-106 Warsaw, Poland; http://orcid.org/0000-0003-3780-083X; Email: [email protected]
Authors
- Ewelina Stefaniak - Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawińskiego 5a, 02-106 Warsaw, Poland
- Dawid Płonka - Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawińskiego 5a, 02-106 Warsaw, Poland; http://orcid.org/0000-0002-4076-9231
- Paulina Szczerba - Chair of Medical Biotechnology, Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland
- Nina E. Wezynfeld - Chair of Medical Biotechnology, Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland
Notes
The authors declare no competing financial interest.

Acknowledgments

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This work was supported by OPUS Grant No. 2018/29/B/ST4/01634 and PRELUDIUM Grant No. 2016/21/N/NZ1/02785 (National Science Centre, Poland). The equipment used was sponsored, in part, by the Centre for Preclinical Research and Technology (CePT), a project cosponsored by the European Regional Development Fund and Innovative Economy, The National Cohesion Strategy of Poland.

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Portelius, E.; Bogdanovic, N.; Gustavsson, M. K.; Volkmann, I.; Brinkmalm, G.; Zetterberg, H.; Winblad, B.; Blennow, K. Mass Spectrometric Characterization of Brain Amyloid Beta Isoform Signatures in Familial and Sporadic Alzheimer’s Disease. Acta Neuropathol. 2010, 120 (2), 185– 193, DOI: 10.1007/s00401-010-0690-1
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Mass spectrometric characterization of brain amyloid beta isoform signatures in familial and sporadic Alzheimer's disease
Portelius, Erik; Bogdanovic, Nenad; Gustavsson, Mikael K.; Volkmann, Inga; Brinkmalm, Gunnar; Zetterberg, Henrik; Winblad, Bengt; Blennow, Kaj
Acta Neuropathologica (2010), 120 (2), 185-193CODEN: ANPTAL; ISSN:0001-6322. (Springer)
A proposed key event in the pathogenesis of Alzheimer's disease (AD) is the formation of neurotoxic amyloid β (Aβ) oligomers and amyloid plaques in specific brain regions that are affected by the disease. The main plaque component is the 42 amino acid isoform of Αβ (Aβ1-42), which is thought to initiate plaque formation and AD pathogenesis. Numerous isoforms of Aβ, e.g., Aβ1-42, Aβ1-40 and the 3-pyroglutamate derivate of Aβ3-42 (pGluAβ3-42), have been detected in the brains of sporadic AD (SAD) and familial AD (FAD) subjects. However, the relative importance of these isoforms in the pathogenesis of AD is not fully understood. Here, we report a detailed study using immunopptn. in combination with mass spectrometric anal. to det. the Aβ isoform pattern in the cerebellum, cortex and hippocampus in AD, including subjects with a mutation in the presenilin (M146V) or amyloid precursor protein (KM670/671NL) genes, SAD subjects and non-demented controls. We show that the dominating Aβ isoforms in the three different brain regions analyzed from control, SAD, and FAD are Aβ1-42, pGluAβ3-42, Aβ4-42 and Aβ1-40 of which Aβ1-42 and Aβ4-42 are the dominant isoforms in the hippocampus and the cortex in all groups analyzed, controls included. No prominent differences in Aβ isoform patterns between FAD and SAD patients were seen, underscoring the similarity in the amyloid pathol. of these two disease entities.
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Alies, B.; Renaglia, E.; Rózga, M.; Bal, W.; Faller, P.; Hureau, C. Cu(II) Affinity for the Alzheimer’s Peptide: Tyrosine Fluorescence Studies Revisited. Anal. Chem. 2013, 85 (3), 1501– 1508, DOI: 10.1021/ac302629u
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Cu(II) Affinity for the Alzheimer's Peptide: Tyrosine Fluorescence Studies Revisited
Alies, Bruno; Renaglia, Emelyne; Rozga, Malgorzata; Bal, Wojciech; Faller, Peter; Hureau, Christelle
Analytical Chemistry (Washington, DC, United States) (2013), 85 (3), 1501-1508CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
Copper(II) binding to the amyloid-β peptide has been proposed to be a key event in the cascade leading to Alzheimer's disease. As a direct consequence, the strength of the Cu(II) to Aβ interaction, i.e., the Cu(II) affinity of Aβ, is a very important parameter to det. Because Aβ peptide contain one Tyr fluorophore in its sequence and because Cu(II) does quench Tyr fluorescence, fluorescence measurements appear to be a straightforward way to obtain this parameter. However, this proved to be wrong, mainly because of data misinterpretation in some previous studies that lead to a conflicting situation. In the present paper, we have investigated in details a large set of fluorescence data that were analyzed with a new method taking into account the presence of two Cu(II) sites and the inner-filter effect. This leads to reinterpretation of the published data and to the detn. of a unified affinity value in the 1010 M-1 range.
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Young, T. R.; Kirchner, A.; Wedd, A. G.; Xiao, Z. An Integrated Study of the Affinities of the Aβ16 Peptide for Cu(I) and Cu(II): Implications for the Catalytic Production of Reactive Oxygen Species. Metallomics 2014, 6 (3), 505– 517, DOI: 10.1039/C4MT00001C
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An integrated study of the affinities of the Aβ16 peptide for Cu(i) and Cu(ii): implications for the catalytic production of reactive oxygen species
Young, Tessa R.; Kirchner, Angie; Wedd, Anthony G.; Xiao, Zhiguang
Metallomics (2014), 6 (3), 505-517CODEN: METAJS; ISSN:1756-591X. (Royal Society of Chemistry)
A new fluorescent probe Aβ16wwa based upon the Aβ16 peptide has been developed with two orders of magnitude greater fluorescence intensity for sensitive detection of interactions with Cu(ii). In combination with the Cu(i) probe Ferene S, it is confirmed that the Aβ16 peptide binds either Cu(i) or Cu(ii) with comparable affinities at pH 7.4 (log KID = -10.4; log KIID = -10.0). It follows from this property that the Cu-Aβ16 complex is a robust if slow catalyst for the aerial oxidn. of ascorbate with H2O2 as primary product (initial rate, ∼0.63 min-1 for Cu-Aβ16 vs. >2.5 min-1 for Cuaq2+). An integrated study of variants of this peptide identifies the major ligands and binding modes involved in its copper complexes in soln. The dependence of KID upon pH is consistent with a two-coordinate Cu(i) site in which dynamic processes exchange Cu(i) between the three available pairs of imidazole sidechains provided by His6, His13 and His14. The N-terminal amine is not involved in Cu(i) binding but is a key ligand for Cu(ii). Acetylation of the N-terminus alters the redox thermodn. gradient for the Cu center and suppresses its catalytic activity considerably. The data indicate the presence of dynamic processes that exchange Cu(ii) between the three His ligands and backbone amide at physiol. pH. His6 is identified as a key ligand for catalysis as its presence minimizes the pre-organization energy required for interchange of the two copper redox sites. These new thermodn. data strengthen structural interpretations for the Cu-Aβ complexes and provide valuable insights into the mol. mechanism by which copper chem. may induce oxidative stress in Alzheimer's disease.
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Conte-Daban, A.; Borghesani, V.; Sayen, S.; Guillon, E.; Journaux, Y.; Gontard, G.; Lisnard, L.; Hureau, C. Link between Affinity and Cu(II) Binding Sites to Amyloid-β Peptides Evaluated by a New Water-Soluble UV-Visible Ratiometric Dye with a Moderate Cu(II) Affinity. Anal. Chem. 2017, 89 (3), 2155– 2162, DOI: 10.1021/acs.analchem.6b04979
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Link between Affinity and Cu(II) Binding Sites to Amyloid-β Peptides Evaluated by a New Water-Soluble UV-Visible Ratiometric Dye with a Moderate Cu(II) Affinity
Conte-Daban, Amandine; Borghesani, Valentina; Sayen, Stephanie; Guillon, Emmanuel; Journaux, Yves; Gontard, Geoffrey; Lisnard, Laurent; Hureau, Christelle
Analytical Chemistry (Washington, DC, United States) (2017), 89 (3), 2155-2162CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
Being able to easily det. the Cu(II) affinity for biomols. of moderate affinity is important. Such biomols. include amyloidogenic peptides, such as the known amyloid-β peptide involved in Alzheimer's disease. Here, the authors report the synthesis of a new water-sol. ratiometric Cu(II) dye with a moderate affinity (109 M-1 at pH 7.1) and the characterizations of the Cu(II) corresponding complex by x-ray crystallog., EPR, and XAS spectroscopic methods. UV-visible competition was performed on the Aβ peptide as well as on a wide series of modified peptides, leading to an affinity value of 1.6 × 109 M-1 at pH 7.1 for the Aβ peptide and to a coordination model for the Cu(II) site within the Aβ peptide that agrees with the one mostly accepted currently.
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Cheignon, C.; Jones, M.; Atrián-Blasco, E.; Kieffer, I.; Faller, P.; Collin, F.; Hureau, C. Identification of Key Structural Features of the Elusive Cu–Aβ Complex That Generates ROS in Alzheimer’s Disease. Chem. Sci. 2017, 8 (7), 5107– 5118, DOI: 10.1039/C7SC00809K
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Identification of key structural features of the elusive Cu-Aβ complex that generates ROS in Alzheimer's disease
Cheignon, Clemence; Jones, Megan; Atrian-Blasco, Elena; Kieffer, Isabelle; Faller, Peter; Collin, Fabrice; Hureau, Christelle
Chemical Science (2017), 8 (7), 5107-5118CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
Oxidative stress is linked to the etiol. of Alzheimer's disease (AD), the most common cause of dementia in the elderly. Redox active metal ions such as copper catalyze the prodn. of Reactive Oxygen Species (ROS) when bound to the amyloid-β (Aβ) peptide encountered in AD. We propose that this reaction proceeds through a low-populated Cu-Aβ state, denoted the "catalytic in-between state" (CIBS), which is in equil. with the resting state (RS) of both Cu(I)-Aβ and Cu(II)-Aβ. The nature of this CIBS is investigated in the present work. We report the use of complementary spectroscopic methods (X-ray absorption spectroscopy, EPR and NMR) to characterize the binding of Cu to a wide series of modified peptides in the RS. ROS prodn. by the resulting Cu-peptide complexes was evaluated using fluorescence and UV-vis based methods and led to the identification of the amino acid residues involved in the Cu-Aβ CIBS species. In addn., a possible mechanism by which the ROS are produced is also proposed. These two main results are expected to affect the current vision of the ROS prodn. mechanism by Cu-Aβ but also in other diseases involving amyloidogenic peptides with weakly structured copper binding sites.
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Cheignon, C.; Faller, P.; Testemale, D.; Hureau, C.; Collin, F. Metal-Catalyzed Oxidation of Aβ and the Resulting Reorganization of Cu Binding Sites Promote ROS Production. Metallomics 2016, 8 (10), 1081– 1089, DOI: 10.1039/C6MT00150E
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Metal-catalyzed oxidation of Aβ and the resulting reorganization of Cu binding sites promote ROS production
Cheignon, Clemence; Faller, Peter; Testemale, Denis; Hureau, Christelle; Collin, Fabrice
Metallomics (2016), 8 (10), 1081-1089CODEN: METAJS; ISSN:1756-591X. (Royal Society of Chemistry)
In the context of Alzheimer's disease (AD), the prodn. of HO • by copper-amyloid beta (Aβ) in the presence of ascorbate is known to be deleterious for the Aβ peptide itself and also for the surrounding mols., thus establishing a direct link between AD and oxidative stress. The metal-catalyzed oxidn. (MCO) of Aβ primarily targets the residues involved in copper coordination during HO • prodn. In the present work, we demonstrate that the oxidative damage undergone by Aβ during MCO lead to a change in copper coordination, with enhanced catalytic properties that increases the rates of ascorbate consumption and HO • prodn., and the amt. of HO • released by the system. This phenomenon is obsd. after the peptide has been sufficiently oxidized.
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Cheignon, C.; Tomas, M.; Bonnefont-Rousselot, D.; Faller, P.; Hureau, C.; Collin, F. Oxidative Stress and the Amyloid Beta Peptide in Alzheimer’s Disease. Redox Biol. 2018, 14, 450– 464, DOI: 10.1016/j.redox.2017.10.014
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Oxidative stress and the amyloid beta peptide in Alzheimer's disease
Cheignon, C.; Tomas, M.; Bonnefont-Rousselot, D.; Faller, P.; Hureau, C.; Collin, F.
Redox Biology (2018), 14 (), 450-464CODEN: RBEIB3; ISSN:2213-2317. (Elsevier B.V.)
A review. Oxidative stress is known to play an important role in the pathogenesis of a no. of diseases. In particular, it is linked to the etiol. of Alzheimer's disease (AD), an age-related neurodegenerative disease and the most common cause of dementia in the elderly. Histopathol. hallmarks of AD are intracellular neurofibrillary tangles and extracellular formation of senile plaques composed of the amyloid-beta peptide (Aβ) in aggregated form along with metal-ions such as copper, iron or zinc. Redox active metal ions, as for example copper, can catalyze the prodn. of Reactive Oxygen Species (ROS) when bound to the amyloid-β (Aβ). The ROS thus produced, in particular the hydroxyl radical which is the most reactive one, may contribute to oxidative damage on both the Aβ peptide itself and on surrounding mol. (proteins, lipids, ...). This review highlights the existing link between oxidative stress and AD, and the consequences towards the Aβ peptide and surrounding mols. in terms of oxidative damage. In addn., the implication of metal ions in AD, their interaction with the Aβ peptide and redox properties leading to ROS prodn. are discussed, along with both in vitro and in vivo oxidn. of the Aβ peptide, at the mol. level.
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Mital, M.; Wezynfeld, N. E.; Frączyk, T.; Wiloch, M. Z.; Wawrzyniak, U. E.; Bonna, A.; Tumpach, C.; Barnham, K. J.; Haigh, C. L.; Bal, W.; Drew, S. C. A Functional Role for Aβ in Metal Homeostasis? N-Truncation and High-Affinity Copper Binding. Angew. Chem., Int. Ed. 2015, 54 (36), 10460– 10464, DOI: 10.1002/anie.201502644
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A Functional Role for Aβ in Metal Homeostasis? N-Truncation and High-Affinity Copper Binding
Mital, Mariusz; Wezynfeld, Nina E.; Fraczyk, Tomasz; Wiloch, Magdalena Z.; Wawrzyniak, Urszula E.; Bonna, Arkadiusz; Tumpach, Carolin; Barnham, Kevin J.; Haigh, Cathryn L.; Bal, Wojciech; Drew, Simon C.
Angewandte Chemie, International Edition (2015), 54 (36), 10460-10464CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
Accumulation of the β-amyloid (Aβ) peptide in extracellular senile plaques rich in copper and zinc is a defining pathol. feature of Alzheimer's disease (AD). The Aβ1-x (x=16/28/40/42) peptides have been the primary focus of CuII binding studies for more than 15 years; however, the N-truncated Aβ4-42 peptide is a major Aβ isoform detected in both healthy and diseased brains, and it contains a novel N-terminal FRH sequence. Proteins with His at the third position are known to bind CuII avidly, with conditional log K values at pH 7.4 in the range of 11.0-14.6, which is much higher than that detd. for Aβ1-x peptides. By using Aβ4-16 as a model, it was demonstrated that its FRH sequence stoichiometrically binds CuII with a conditional Kd value of 3×10-14 M at pH 7.4, and that both Aβ4-16 and Aβ4-42 possess negligible redox activity. Combined with the predominance of Aβ4-42 in the brain, our results suggest a physiol. role for this isoform in metal homeostasis within the central nervous system.
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Harford, C.; Sarkar, B. Amino Terminal Cu(II)- and Ni(II)-Binding (ATCUN) Motif of Proteins and Peptides: Metal Binding, DNA Cleavage, and Other Properties. Acc. Chem. Res. 1997, 30 (3), 123– 130, DOI: 10.1021/ar9501535
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Amino Terminal Cu(II)- and Ni(II)-Binding Motif of Proteins and Peptides: Metal Binding, DNA Cleavage, and Other Properties
Harford, Catherine; Sarkar, Bibudhendra
Accounts of Chemical Research (1997), 30 (3), 123-130CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
A review, with 74 refs., on the amino terminal Cu(II)- and Ni(II)-binding ATCUN (motif). The ATCUN motif is a structural feature which can be defined as being present in a protein or peptide which has (1) a free NH2-terminus, (2) a histidine residue in the third position, and (3) two intervening peptide nitrogens. Topics include the origin of the ATCUN motif from the early characterization of the metal-binding properties within albumins, mol. design of the ATCUN motif, DNA cleavage properties of the ATCUN motif, use of the motif in protein design for the specific DNA cleavage, and prediction of naturally occurring proteins with the ATCUN motif.
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Stefaniak, E.; Bal, W. Binding Properties of N-Truncated Aβ Peptides: In Search of Biological Function. Inorg. Chem. 2019, 58 (20), 13561– 13577, DOI: 10.1021/acs.inorgchem.9b01399
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CuII binding properties of N-truncated Aβ peptides: In search of biological function
Stefaniak, Ewelina; Bal, Wojciech
Inorganic Chemistry (2019), 58 (20), 13561-13577CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
A review. As life expectancy increases, the no. of people affected by progressive and irreversible dementia, Alzheimer's Disease (AD), is predicted to grow. No drug designs seem to be working in humans, apparently because the origins of AD have not been identified. Invoking amyloid cascade, metal ions, and ROS prodn. hypothesis of AD, herein we share our point of view on Cu(II) binding properties of Aβ4-x, the most prevalent N-truncated Aβ peptide, currently known as the main constituent of amyloid plaques. The capability of Aβ4-x to rapidly take over copper from previously tested Aβ1-x peptides and form highly stable complexes, redox unreactive and resistant to copper exchange reactions, prompted us to propose physiol. roles for these peptides. We discuss the new findings on the reactivity of Cu(II)Aβ4-x with coexisting biomols. in the context of synaptic cleft; we suggest that the role of Aβ4-x peptides is to quench Cu(II) toxicity in the brain and maintain neurotransmission.
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Hopt, A.; Korte, S.; Fink, H.; Panne, U.; Niessner, R.; Jahn, R.; Kretzschmar, H.; Herms, J. Methods for Studying Synaptosomal Copper Release. J. Neurosci. Methods 2003, 128 (1), 159– 172, DOI: 10.1016/S0165-0270(03)00173-0
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Methods for studying synaptosomal copper release
Hopt, Alexander; Korte, Stefan; Fink, Herbert; Panne, Ulrich; Niessner, Reinhard; Jahn, Reinhard; Kretzschmar, Hans; Herms, Jochen
Journal of Neuroscience Methods (2003), 128 (1,2), 159-172CODEN: JNMEDT; ISSN:0165-0270. (Elsevier Science B.V.)
Cu is thought to play an important role in the pathogenesis of several neurodegenerative diseases, such as Wilson's, Alzheimer's, and probably in prion protein diseases like Creutzfeldt-Jakob's disease. Until now, no method existed to det. the concn. of this cation in vivo. Here, we present two possible approaches combined with a crit. comparison of the results. The successful use of fluorescent ligands for the detn. of Ca2+-concns. in recent years encouraged us to seek a fluorophore which specifically reacts to Cu2+ and to characterize it for our purposes. We found that the emission of TSPP (tetrakis-(4-sulfophenyl)porphine) at an emission wavelength of 645 nm is in vitro highly specific to Cu2+ (apparent dissocn. const. Kd=0.43±0.07 μM at pH 7.4). It does not react with the most common divalent cations in the brain, Ca2+ and Mg2+, unlike most of the other dyes examd. In addn., Zn2+ quenches TSPP fluorescence at a different emission wavelength (605 nm) with a Kd of 50±2.5 μM (pH 7.0). With these findings, we applied the measurement of Cu with TSPP to a biol. system, showing for the first time in vivo that there is release of copper by synaptosomes upon depolarization. Our findings were validated with a completely independent anal. approach based on ICP-MS (inductively-coupled-plasma mass-spectrometry).
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Shibata, M.; Yamada, S.; Kumar, S. R.; Calero, M.; Bading, J.; Frangione, B.; Holtzman, D. M.; Miller, C. A.; Strickland, D. K.; Ghiso, J.; Zlokovic, B. V. Clearance of Alzheimer’s Amyloid-Ss(1–40) Peptide from Brain by LDL Receptor-Related Protein-1 at the Blood-Brain Barrier. J. Clin. Invest. 2000, 106 (12), 1489– 1499, DOI: 10.1172/JCI10498
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Clearance of Alzheimer's amyloid-β1-40 peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier
Shibata, Masayoshi; Yamada, Shinya; Kumar, S. Ram; Calero, Miguel; Bading, James; Frangione, Blas; Holtzman, David M.; Miller, Carol A.; Strickland, Dudley K.; Ghiso, Jorge; Zlokovic, Berislav V.
Journal of Clinical Investigation (2000), 106 (12), 1489-1499CODEN: JCINAO; ISSN:0021-9738. (American Society for Clinical Investigation)
Elimination of amyloid-β peptide (Aβ) from the brain is poorly understood. After intracerebral microinjections in young mice, 125I-Aβ1-40 was rapidly removed from the brain (t1/2 ≤ 25 min), mainly by vascular transport across the blood-brain barrier (BBB). The efflux transport system for Aβ1-40 at the BBB was half satd. at 15.3 nM, and the maximal transport capacity was reached between 70 nM and 100 nM. Aβ1-40 clearance was substantially inhibited by the receptor-assocd. protein, and by antibodies against LDL receptor-related protein-1 (LRP-1) and α2-macroglobulin (α2M). As compared to adult wild-type mice, clearance was significantly reduced in young and old apolipoprotein E (apoE) knockout mice, and in old wild-type mice. There was no evidence that Aβ was metabolized in brain interstitial fluid and degraded to smaller peptide fragments and amino acids before its transport across the BBB into the circulation. LRP-1, although abundant in brain microvessels in young mice, was downregulated in older animals, and this downregulation correlated with regional Aβ accumulation in brains of Alzheimer's disease (AD) patients. The authors conclude that the BBB removes Aβ from the brain largely via age-dependent, LRP-1-mediated transport that is influenced by α2M and/or apoE, and may be impaired in AD.
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Deane, R.; Du Yan, S.; Submamaryan, R. K.; LaRue, B.; Jovanovic, S.; Hogg, E.; Welch, D.; Manness, L.; Lin, C.; Yu, J.; Zhu, H.; Ghiso, J.; Frangione, B.; Stern, A.; Schmidt, A. M.; Armstrong, D. L.; Arnold, B.; Liliensiek, B.; Nawroth, P.; Hofman, F.; Kindy, M.; Stern, D.; Zlokovic, B. RAGE Mediates Amyloid-β Peptide Transport across the Blood-Brain Barrier and Accumulation in Brain. Nat. Med. 2003, 9 (7), 907– 913, DOI: 10.1038/nm890
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RAGE mediates amyloid-β peptide transport across the blood-brain barrier and accumulation in brain
Deane, Rashid; Yan, Shi Du; Submamaryan, Ram Kumar; LaRue, Barbara; Jovanovic, Suzana; Hogg, Elizabeth; Welch, Deborah; Manness, Lawrence; Lin, Chang; Yu, Jin; Zhu, Hong; Ghiso, Jorge; Frangione, Blas; Stern, Alan; Schmidt, Ann Marie; Armstrong, Don L.; Arnold, Bernd; Liliensiek, Birgit; Nawroth, Peter; Hofman, Florence; Kindy, Mark; Stern, David; Zlokovic, Berislav
Nature Medicine (New York, NY, United States) (2003), 9 (7), 907-913CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)
Amyloid-β peptide (Aβ) interacts with the vasculature to influence Aβ levels in the brain and cerebral blood flow, providing a means of amplifying the Aβ-induced cellular stress underlying neuronal dysfunction and dementia. Systemic Aβ infusion and studies in genetically manipulated mice show that Aβ interaction with receptor for advanced glycation end products (RAGE)-bearing cells in the vessel wall results in transport of Aβ across the blood-brain barrier (BBB) and expression of proinflammatory cytokines and endothelin-1 (ET-1), the latter mediating Aβ-induced vasoconstriction. Inhibition of RAGE-ligand interaction suppresses accumulation of Aβ in brain parenchyma in a mouse transgenic model. These findings suggest that vascular RAGE is a target for inhibiting pathogenic consequences of Aβ-vascular interactions, including development of cerebral amyloidosis.
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Paroni, G.; Bisceglia, P.; Seripa, D. Understanding the Amyloid Hypothesis in Alzheimer’s Disease. J. Alzheimer's Dis. 2019, 68 (2), 493– 510, DOI: 10.3233/JAD-180802
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Understanding the Amyloid Hypothesis in Alzheimer's Disease
Paroni, Giulia; Bisceglia, Paola; Seripa, Davide; Solfrizzi, Vincenzo
Journal of Alzheimer's Disease (2019), 68 (2), 493-510CODEN: JADIF9; ISSN:1387-2877. (IOS Press)
A review. The amyloid hypothesis (AH) is still the most accepted model to explain the pathogenesis of inherited Alzheimer's disease (IAD). However, despite the neuropathol. overlapping with the non-inherited form (NIAD), AH waver in explaining NIAD. Thus, 30 years after its first statement several questions are still open, mainly regarding the role of amyloid plaques (AP) and apolipoprotein E (APOE). Accordingly, a pathogenetic model including the role of AP and APOE unifying IAD and NIAD pathogenesis is still missing. In the present understanding of the AH, we suggested that amyloid-β (Aβ) peptides prodn. and AP formation is a physiol. aging process resulting from a systemic age-related decrease in the efficiency of the proteins catabolism/clearance machinery. In this pathogenetic model Aβ peptides act as neurotoxic mols., but only above a crit. concn. [Aβ]c. A threshold mechanism triggers IAD/NIAD onset only when [Aβ]≥[Aβ]c. In this process, APOE modifies [Aβ]c threshold in an isoform-specific way. Consequently, all factors influencing Aβ anabolism, such as amyloid beta precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) gene mutations, and/or Aβ catabolism/clearance could contribute to exceed the threshold [Aβ]c, being characteristic of each individual. In this model, AP formation does not depend on [Aβ]c. The present interpretation of the AH, unifying the pathogenetic theories for IAD and NIAD, will explain why AP and APOE4 may be obsd. in healthy aging and why they are not the cause of AD. It is clear that further studies are needed to confirm our pathogenetic model. Nevertheless, our suggestion may be useful to better understand the pathogenesis of AD.
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Kanemitsu, H.; Tomiyama, T.; Mori, H. Human Neprilysin Is Capable of Degrading Amyloid β Peptide Not Only in the Monomeric Form but Also the Pathological Oligomeric Form. Neurosci. Lett. 2003, 350 (2), 113– 116, DOI: 10.1016/S0304-3940(03)00898-X
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Human neprilysin is capable of degrading amyloid β peptide not only in the monomeric form but also the pathological oligomeric form
Kanemitsu, Hyoe; Tomiyama, Takami; Mori, Hiroshi
Neuroscience Letters (2003), 350 (2), 113-116CODEN: NELED5; ISSN:0304-3940. (Elsevier Science Ltd.)
Amyloid β-peptide (Aβ) is widely believed to play a central role in Alzheimer's disease (AD). Coordinate regulation of cerebral Aβ level is important in the pathogenesis of AD since either increased prodn. of Aβ from amyloid precursor protein or decreased degrdn. causes elevated levels of Aβ, leading to accumulation of cerebral plaque formation or amyloid angiopathy. Here the authors studied neprilysin, a putative proteolytic enzyme for Aβ, and found that it degraded not only monomeric but also oligomeric forms of Aβ1-40. Moreover, neprilysin was found to be capable of degrdn. of the oligomeric form of Aβ1-42, a significant Aβ species in early pathogenesis. Neprilysin to decrease cerebral Aβ is suggested to be inevitable factor as a vital therapeutic target.
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Oefner, C.; Roques, B. P.; Fournie-Zaluski, M.-C.; Dale, G. E. Structural Analysis of Neprilysin with Various Specific and Potent Inhibitors. Acta Crystallogr., Sect. D: Biol. Crystallogr. 2004, 60 (2), 392– 396, DOI: 10.1107/S0907444903027410
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Structural analysis of neprilysin with various specific and potent inhibitors
Oefner, Christian; Roques, Bernard P.; Fournie-Zaluski, Marie Claude; Dale, Glenn E.
Acta Crystallographica, Section D: Biological Crystallography (2004), D60 (2), 392-396CODEN: ABCRE6; ISSN:0907-4449. (Blackwell Publishing Ltd.)
Neutral endopeptidase (NEP) is the major enzyme involved in the metabolic inactivation of a no. of bioactive peptides including the enkephalins, substance P, endothelin, bradykinin, and atrial natriuretic factor. Owing to the physiol. importance of NEP in the modulation of nociceptive and pressor responses, there is considerable interest in inhibitors of this enzyme as novel analgesics and antihypertensive agents. Here, the crystal structures of the sol. extracellular domain of human NEP (residues 52-749) complexed with various potent and competitive inhibitors are described. The structures unambiguously reveal the binding mode of the different zinc-chelating groups and the subsite specificity of the enzyme.
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Mital, M.; Bal, W.; Frączyk, T.; Drew, S. C. Interplay between Copper, Neprilysin, and N-Truncation of β-Amyloid. Inorg. Chem. 2018, 57 (11), 6193– 6197, DOI: 10.1021/acs.inorgchem.8b00391
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Interplay between Copper, Neprilysin, and N-Truncation of β-Amyloid
Mital, Mariusz; Bal, Wojciech; Fraczyk, Tomasz; Drew, Simon C.
Inorganic Chemistry (2018), 57 (11), 6193-6197CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
Sporadic Alzheimer's disease (AD) is assocd. with an inefficient clearance of the β-amyloid (Aβ) peptide from the central nervous system. Protein levels and activity of the Zn2+-dependent endopeptidase, neprilysin (NEP), inversely correlate with brain Aβ levels during ageing and in AD. The present study considered the ability of Cu2+ ions to inhibit human recombinant NEP and the role for NEP in generation of N-truncated Aβ fragments with high-affinity Cu2+ binding motifs that could prevent this inhibition. Cu2+ noncompetitively inhibited NEP (Ki = 1.0 μM) and activity could not be restored by addn. of excess Zn2+, which also leads to NEP inhibition (Ki = 20 μM). Proteolysis of Aβ yielded the sol., non-amyloidogenic Aβ4-9 fragment that bound Cu2+ with femtomolar affinity at pH 7.4. This provided Aβ4-9 with the potential to act as a Cu2+ carrier and to mediate its own prodn. by preventing NEP inhibition. Inhibition by high Zn2+ concns. further suggested a mechanism for modulating NEP activity, Aβ4-9 prodn., and Cu2+ homeostasis.
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Bossak-Ahmad, K.; Mital, M.; Płonka, D.; Drew, S. C.; Bal, W. Oligopeptides Generated by Neprilysin Degradation of β-Amyloid Have the Highest Cu(II) Affinity in the Whole Aβ Family. Inorg. Chem. 2019, 58 (1), 932– 943, DOI: 10.1021/acs.inorgchem.8b03051
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Oligopeptides generated by neprilysin degradation of β-amyloid have the highest Cu(II) affinity in the whole Aβ Family
Bossak-Ahmad, Karolina; Mital, Mariusz; Plonka, Dawid; Drew, Simon C.; Bal, Wojciech
Inorganic Chemistry (2019), 58 (1), 932-943CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
The catabolism of β-amyloid (Aβ) is carried out by numerous endopeptidases including neprilysin, which hydrolyzes peptide bonds preceding positions 4, 10, and 12 to yield Aβ4-9 and a minor Aβ12-x species. Alternative processing of the amyloid precursor protein by β-secretase also generates the Aβ11-x species. All these peptides contain a Xxx-Yyy-His sequence, also known as an ATCUN or NTS motif, making them strong chelators of Cu(II) ions. We synthesized the corresponding peptides, Phe-Arg-His-Asp-Ser-Gly-OH (Aβ4-9), Glu-Val-His-His-Gln-Lys-am (Aβ11-16), Val-His-His-Gln-Lys-am (Aβ12-16), and pGlu-Val-His-His-Gln-Lys-am (pAβ11-16), and investigated their Cu(II) binding properties using potentiometry, and UV-vis, CD, and ESR spectroscopies. We found that the three peptides with unmodified N-termini formed square-planar Cu(II) complexes at pH 7.4 with analogous geometries but significantly varied Kd values of 6.6 fM (Aβ4-9), 9.5 fM (Aβ12-16), and 1.8 pM (Aβ11-16). Cyclization of the N-terminal Glu11 residue to the pyroglutamate species pAβ11-16 dramatically reduced the affinity (5.8 nM). The Cu(II) affinities of Aβ4-9 and Aβ12-16 are the highest among the Cu(II) complexes of Aβ peptides. Using fluorescence spectroscopy, we demonstrated that the Cu(II) exchange between the Phe-Arg-His and Val-His-His motifs is very slow, on the order of days. These results are discussed in terms of the relevance of Aβ4-9, a major Cu(II) binding Aβ fragment generated by neprilysin, as a possible Cu(II) carrier in the brain.
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Deane, R.; Bell, R. D.; Sagare, A.; Zlokovic, B. V. Clearance of Amyloid-Beta Peptide across the Blood-Brain Barrier: Implication for Therapies in Alzheimer’s Disease. CNS Neurol. Disord.: Drug Targets 2009, 8 (1), 16– 30, DOI: 10.2174/187152709787601867
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Clearance of amyloid-β peptide across the blood-brain barrier: implication for therapies in Alzheimer's disease
Deane, R.; Bell, R. D.; Sagare, A.; Zlokovic, B. V.
CNS & Neurological Disorders: Drug Targets (2009), 8 (1), 16-30CODEN: CNDDA3; ISSN:1871-5273. (Bentham Science Publishers Ltd.)
A review. The main receptors for amyloid-beta peptide (Aβ) transport across the blood-brain barrier (BBB) from brain to blood and blood to brain are low-d. lipoprotein receptor related protein-1 (LRP1) and receptor for advanced glycation end products (RAGE), resp. In normal human plasma a sol. form of LRP1 (sLRP1) is a major endogenous brain Aβ 'sinker' that sequesters some 70 to 90 % of plasma Aβ peptides. In Alzheimer's disease (AD), the levels of sLRP1 and its capacity to bind Aβ are reduced which increases free Aβ fraction in plasma. This in turn may increase brain Aβ burden through decreased Aβ efflux and/or increased Aβ influx across the BBB. In Aβ immunotherapy, anti-Aβ antibody sequestration of plasma Aβ enhances the peripheral Aβ 'sink action'. However, in contrast to endogenous sLRP1 which does not penetrate the BBB, some anti-Aβ antibodies may slowly enter the brain which reduces the effectiveness of their sink action and may contribute to neuroinflammation and intracerebral hemorrhage. Anti-Aβ antibody/Aβ immune complexes are rapidly cleared from brain to blood via FcRn (neonatal Fc receptor) across the BBB. In a mouse model of AD, restoring plasma sLRP1 with recombinant LRP-IV cluster reduces brain Aβ burden and improves functional changes in cerebral blood flow (CBF) and behavioral responses, without causing neuroinflammation and/or hemorrhage. The C-terminal sequence of Aβ is required for its direct interaction with sLRP and LRP-IV cluster which is completely blocked by the receptor-assocd. protein (RAP) that does not directly bind Aβ. Therapies to increase LRP1 expression or reduce RAGE activity at the BBB and/or restore the peripheral Aβ 'sink' action, hold potential to reduce brain Aβ and inflammation, and improve CBF and functional recovery in AD models, and by extension in AD patients.
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Maher, P. The Effects of Stress and Aging on Glutathione Metabolism. Ageing Res. Rev. 2005, 4 (2), 288– 314, DOI: 10.1016/j.arr.2005.02.005
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The effects of stress and aging on glutathione metabolism
Maher, Pamela
Ageing Research Reviews (2005), 4 (2), 288-314CODEN: ARRGAK; ISSN:1568-1637. (Elsevier B.V.)
A review. Glutathione plays a crit. role in many biol. processes both directly as a co-factor in enzymic reactions and indirectly as the major thiol-disulfide redox buffer in mammalian cells. Glutathione also provides a crit. defense system for the protection of cells from many forms of stress. However, mild stress generally increases glutathione levels, often but not exclusively through effects on glutamate cysteine ligase, the rate-limiting enzyme for glutathione biosynthesis. This upregulation in glutathione provides protection from more severe stress and may be a crit. feature of preconditioning and tolerance. In contrast, during aging, glutathione levels appear to decline in a no. of tissues, thereby putting cells at increased risk of succumbing to stress. The evidence for such a decline is strongest in the brain where glutathione loss is implicated in both Parkinson's disease and in neuronal injury following stroke.
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Sies, H. Glutathione and Its Role in Cellular Functions. Free Radical Biol. Med. 1999, 27, 916, DOI: 10.1016/S0891-5849(99)00177-X
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Glutathione and its role in cellular functions
Sies, Helmut
Free Radical Biology & Medicine (1999), 27 (9/10), 916-921CODEN: FRBMEH; ISSN:0891-5849. (Elsevier Science Inc.)
A review, with ∼114 refs. Glutathione (GSH) is the major cellular thiol participating in cellular redox reactions and thioether formation. This article serves as introduction to the FRBM Forum on glutathione and emphasizes cellular functions: What is GSH. Where does it come from. Where does it go. What does it do. What is new and noteworthy. Research tools, historical remarks, and links to current trends.
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Hatori, Y.; Lutsenko, S. The Role of Copper Chaperone Atox1 in Coupling Redox Homeostasis to Intracellular Copper Distribution. Antioxidants 2016, 5 (3), 25, DOI: 10.3390/antiox5030025
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The role of copper chaperone Atox1 in coupling redox homeostasis to intracellular copper distribution
Hatori, Yuta; Lutsenko, Svetlana
Antioxidants (2016), 5 (3), 25/1-25/16CODEN: ANTIGE; ISSN:2076-3921. (MDPI AG)
A review. Human antioxidant protein 1 (Atox1) is a small cytosolic protein with an essential role in copper homeostasis. Atox1 functions as a copper carrier facilitating copper transfer to the secretory pathway. This process is required for activation of copper dependent enzymes involved in neurotransmitter biosynthesis, iron efflux, neovascularization, wound healing, and regulation of blood pressure. Recently, new cellular roles for Atox1 have emerged. Changing levels of Atox1 were shown to modulate response to cancer therapies, contribute to inflammatory response, and protect cells against various oxidative stresses. It has also become apparent that the activity of Atox1 is tightly linked to the cellular redox status. In this review, we summarize biochem. information related to a dual role of Atox1 as a copper chaperone and an antioxidant. We discuss how these two activities could be linked and contribute to establishing the intracellular copper balance and functional identity of cells during differentiation.
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Maryon, E. B.; Molloy, S. A.; Kaplan, J. H. Cellular Glutathione Plays a Key Role in Copper Uptake Mediated by Human Copper Transporter 1. Am. J. Physiol. Cell Physiol. 2013, 304 (8), C768– C779, DOI: 10.1152/ajpcell.00417.2012
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Bachhawat, A. K.; Thakur, A.; Kaur, J.; Zulkifli, M. Glutathione Transporters. Biochim. Biophys. Acta, Gen. Subj. 2013, 1830 (5), 3154– 3164, DOI: 10.1016/j.bbagen.2012.11.018
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Glutathione transporters
Bachhawat, Anand K.; Thakur, Anil; Kaur, Jaspreet; Zulkifli, M.
Biochimica et Biophysica Acta, General Subjects (2013), 1830 (5), 3154-3164CODEN: BBGSB3; ISSN:0304-4165. (Elsevier B.V.)
A review. Glutathione (I) is synthesized in the cytoplasm, but there is a requirement for I not only in the cytoplasm, but in the other organelles and the extracellular milieu. I is also imported into the cytoplasm. The transport of I across these different membranes in different systems have been biochem. demonstrated. However the mol. identity of the transporters has been established only in a few cases. Here, an attempt is made to present the current state of knowledge of I transporters from different organisms as well as different organelles. These include the most well-characterized transporters, the yeast high-affinity, high-specificity I transporters involved in import into the cytoplasm, and the mammalian MRP proteins involved in low affinity I efflux from the cytoplasm. Other I transporters that have been described either with direct or indirect evidences are also discussed. The mol. identity of a few I transporters has been unambiguously established, but there is a need to identify the transporters of other systems and organelles. There is a lack of direct evidence establishing transport by suggested transporters in many cases. Studies with the high affinity transporters have led to important structure-function insights. An understanding of I transporters is crit. to an understanding of redox homeostasis in living cells. By presenting the current state of understanding and gaps in knowledge, the authors hope to stimulate research in these fields.
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Santoro, A.; Ewa Wezynfeld, N.; Vašák, M.; Bal, W.; Faller, P. Cysteine and Glutathione Trigger the Cu-Zn Swap between Cu(II)-Amyloid-Β4–16 Peptide and Zn7-Metallothionein-3. Chem. Commun. 2017, 53 (85), 11634– 11637, DOI: 10.1039/C7CC06802F
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Cysteine and glutathione trigger the Cu-Zn swap between Cu(II)-amyloid-β4-16 peptide and Zn7-metallothionein-3
Santoro, Alice; Ewa Wezynfeld, Nina; Vasak, Milan; Bal, Wojciech; Faller, Peter
Chemical Communications (Cambridge, United Kingdom) (2017), 53 (85), 11634-11637CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
Cysteine and glutathione are able to reduce Cu(II) coordinated to the peptide amyloidβ4-16, and shuttle the resulting Cu(I) to partially replace Zn(II) in the protein Zn7-metallothionein-3 complex. The released Zn(II) in turn binds to amyloid-β4-16. Thus, cysteine and glutathione are modulators of Cu/Zn-distribution between metallothionein-3 and amyloid-β4-16.
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Morgan, M. T.; Nguyen, L. A. H.; Hancock, H. L.; Fahrni, C. J. Glutathione Limits Aquacopper(I) to Sub-Femtomolar Concentrations through Cooperative Assembly of a Tetranuclear Cluster. J. Biol. Chem. 2017, 292 (52), 21558– 21567, DOI: 10.1074/jbc.M117.817452
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Glutathione limits aquacopper(I) to sub-femtomolar concentrations through cooperative assembly of a tetranuclear cluster
Morgan, M. Thomas; Nguyen, Lily Anh H.; Hancock, Haylie L.; Fahrni, Christoph J.
Journal of Biological Chemistry (2017), 292 (52), 21558-21567CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
The tripeptide glutathione (GSH) is a crucial intracellular reductant and radical scavenger, but it may also coordinate the soft Cu(I) cation and thereby yield pro-oxidant species. The GSH-Cu(I) interaction is thus a key consideration for both redox and copper homeostasis in cells. However, even after nearly four decades of investigation, the nature and stability of the GSH-Cu(I) complexes formed under biol. relevant conditions remain controversial. Here, we revealed the unexpected predominance of a tetranuclear [Cu4(GS)6] cluster that is sufficiently stable to limit the effective free aquacopper(I) concn. to the sub-femtomolar regime. Combined spectrophotometric-potentiometric titrns. at biol. realistic GSH/Cu(I) ratios, enabled by our recently developed Cu(I) affinity stds. and corroborated by low-temp. phosphorescence studies, established cooperative assembly of [Cu4(GS)6] as the dominant species over a wide pH range, from 5.5 to 7.5. Our robust model for the glutathione-Cu(I) equil. system sets a firm upper limit on the thermodn. availability of intracellular copper that is 3 orders of magnitude lower than previously estd. Taking into account their ability to catalyze the prodn. of deleterious superoxide, the formation of Cu(I)-glutathione complexes might be avoided under normal physiol. conditions. The actual intracellular Cu(I) availability may thus be regulated a further 3 orders of magnitude below the GSH/Cu(I) affinity limit, consistent with the most recent affinity detns. of Cu(I) chaperones.
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Speisky, H.; Gómez, M.; Carrasco-Pozo, C.; Pastene, E.; Lopez-Alarcón, C.; Olea-Azar, C. Cu(I)–Glutathione Complex: A Potential Source of Superoxide Radicals Generation. Bioorg. Med. Chem. 2008, 16 (13), 6568– 6574, DOI: 10.1016/j.bmc.2008.05.026
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Cu(I)-Glutathione complex: A potential source of superoxide radicals generation
Speisky, Hernan; Gomez, Maritza; Carrasco-Pozo, Catalina; Pastene, Edgar; Lopez-Alarcon, Camilo; Olea-Azar, Claudio
Bioorganic & Medicinal Chemistry (2008), 16 (13), 6568-6574CODEN: BMECEP; ISSN:0968-0896. (Elsevier Ltd.)
Cu2+ ions and GSH mols. interact swiftly to form the complex Cu(I)-glutathione. We investigated the potential capacity of such complex to reduce mol. oxygen. The addn. of SOD to a soln. contg. Cu(I)-glutathione led to a sustained decline of the basal oxygen level. Such effect was partially reverted by the addn. of catalase. The complex was able to induce the redn. of cytochrome c and the oxidn. of dihydroethidium into 2-hydroxyethidium. Both effects were totally blocked by SOD. The ability of the complex to generate superoxide radicals was confirmed by EPR spin-trapping. Cu(I)-glutathione induces no oxidn. of fluorescein, a hydroxyl radical-sensitive probe. We conclude that in solns. contg. the complex, oxygen is continually reduced into superoxide, and that-in absence of interceptors-the latter radicals are quant. re-oxidized into mol. oxygen. We suggest that, by functioning as a continuous source of superoxide, the complex could potentially affect a broad range of susceptible biol. targets.
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Várnagy, K.; Sóvágó, I.; Kozłowski, H. Transition Metal Complexes of Amino Acids and Derivatives Containing Disulphide Bridges. Inorg. Chim. Acta 1988, 151 (2), 117– 123, DOI: 10.1016/S0020-1693(00)91891-7
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Transition metal complexes of amino acids and derivatives containing disulfide bridges
Varnagy, Katalin; Sovago, Imre; Kozlowski, Henryk
Inorganica Chimica Acta (1988), 151 (2), 117-23CODEN: ICHAA3; ISSN:0020-1693.
The interaction of Co(II), Ni(II), Cu(II), and Zn with D-penicillamine disulfide, oxidized glutathione, and L-cysteinyglycine disulfide were studied by using pH-metric, spectrophotometric, and ESR methods. D-Penicillamine disulfide forms binuclear complexes with all the metal ions studied. The formation of 1:1 complexes is characteristic of oxidized glutathione. L-Cysteinylglycine disulfide behaves like dipeptides, but the presence of 2 sep. peptide moieties also results in the formation of various binuclear complexes. Metal ion-disulfide binding was not obsd. in any case.
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Meloni, G.; Faller, P.; Vašák, M. Redox Silencing of Copper in Metal-Linked Neurodegenerative Disorders: Reaction of Zn7metallothionein-3 with Cu2+ Ions. J. Biol. Chem. 2007, 282 (22), 16068– 16078, DOI: 10.1074/jbc.M701357200
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Redox Silencing of Copper in Metal-linked Neurodegenerative Disorders: Reaction of Zn7metallothionein-3 with Cu2+ ions
Meloni, Gabriele; Faller, Peter; Vasak, Milan
Journal of Biological Chemistry (2007), 282 (22), 16068-16078CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
Dysregulation of copper and zinc homeostasis in the brain plays a crit. role in Alzheimer disease (AD). Copper binding to amyloid-β peptide (Aβ) is linked with the neurotoxicity of Aβ and free radical damage. Metallothionein-3 (MT-3) is a small cysteine- and metal-rich protein expressed in the brain and found down-regulated in AD. This protein occurs intra- and extracellularly, and it plays an important role in the metab. of zinc and copper. In cell cultures Zn7MT-3, by an unknown mechanism, protects neurons from the toxicity of Aβ. We have, therefore, used a range of complementary spectroscopic and biochem. methods to characterize the interaction of Zn7MT-3 with free Cu2+ ions. We show that Zn7MT-3 scavenges free Cu2+ ions through their redn. to Cu+ and binding to the protein. In this reaction thiolate ligands are oxidized to disulfides concomitant with Zn2+ release. The binding of the first four Cu2+ is cooperative forming a Cu(I)4-thiolate cluster in the N-terminal domain of Cu4,Zn4MT-3 together with two disulfides bonds. The Cu4-thiolate cluster exhibits an unusual stability toward air oxygen. The results of UV-visible, CD, and Cu(I) phosphorescence at 77 K suggest the existence of metal-metal interactions in this cluster. We have demonstrated that Zn7MT-3 in the presence of ascorbate completely quenches the copper-catalyzed hydroxyl radical (OH•) prodn. Thus, zinc-thiolate clusters in Zn7MT-3 can efficiently silence the redox-active free Cu2+ ions. The biol. implication of our studies as to the protective role of Zn7MT-3 from the Cu2+ toxicity in AD and other neurodegenerative disorders is discussed.
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Wezynfeld, N. E.; Stefaniak, E.; Stachucy, K.; Drozd, A.; Płonka, D.; Drew, S. C.; Krężel, A.; Bal, W. Resistance of Cu(Aβ4–16) to Copper Capture by Metallothionein-3 Supports a Function for the Aβ4–42 Peptide as a Synaptic CuIIScavenger. Angew. Chem., Int. Ed. 2016, 55 (29), 8235– 8238, DOI: 10.1002/anie.201511968
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Resistance of Cu(Aβ4-16) to copper capture by metallothionein-3 supports a function for the Aβ4-42 peptide as a synaptic CuII scavenger
Wezynfeld, Nina E.; Stefaniak, Ewelina; Stachucy, Kinga; Drozd, Agnieszka; Plonka, Dawid; Drew, Simon C.; Krezel, Artur; Bal, Wojciech
Angewandte Chemie, International Edition (2016), 55 (29), 8235-8238CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
Aβ4-42 is a major species of amyloid-β (Aβ) peptide in the brains of both healthy individuals and those affected by Alzheimer's disease. It has recently been demonstrated to bind Cu2+ with an affinity ∼3000-fold higher than the commonly studied Aβ1-42 and Aβ1-40 peptides, which are implicated in the pathogenesis of Alzheimer's disease. Metallothionein-3, a protein considered to orchestrate Cu2+ and Zn2+ metab. in the brain and provide antioxidant protection, was shown to ext. Cu2+ from Aβ1-40 when acting in its native Zn7MT-3 form. This reaction is assumed to underlie the neuroprotective effect of Zn7MT-3 against Aβ toxicity. Here, the authors used truncated model peptides Aβ1-16 and Aβ4-16 to demonstrate that the high-affinity Cu2+ complex of Aβ4-16 is resistant to Zn7MT-3 reactivity. This indicated that the analogous complex of the full-length peptide, Cu(Aβ4-42), will not yield Cu2+ to MT-3 in the brain, thus supporting the concept of a physiol. role for Aβ4-42 as a Cu2+ scavenger in the synaptic cleft.
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Santoro, A.; Wezynfeld, N.; Stefaniak, E.; Pomorski, A.; Płonka, D.; Krezel, A.; Bal, W.; Faller, P. Cu Transfer from Amyloid-Β4–16 to Metallothionein-3: The Role of Neurotransmitter Glutamate and Metallothionein-3 Zn(II)-Load States. Chem. Commun. 2018, 54, 12634– 12637, DOI: 10.1039/C8CC06221H
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Cu transfer from amyloid-β4-16 to metallothionein-3: the role of the neurotransmitter glutamate and metallothionein-3 Zn(II)-load states
Santoro, Alice; Wezynfeld, Nina Ewa; Stefaniak, Ewelina; Pomorski, Adam; Plonka, Dawid; Krezel, Artur; Bal, Wojciech; Faller, Peter
Chemical Communications (Cambridge, United Kingdom) (2018), 54 (89), 12634-12637CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
Copper transfer from Cu(II)amyloid-β4-16 to human Zn7-metallothionein-3 can be accelerated by glutamate and by lowering the Zn-load of metallothionein-3 with EDTA. Glutamate facilitates the Cu(II) release, and Zn4-6-metallothionein-3 react more rapidly. These mechanisms are additive, proving the intricate and interconnected network of zinc and copper trafficking between biomols.
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Ngamchuea, K.; Batchelor-McAuley, C.; Compton, R. G. The Copper(II)-Catalyzed Oxidation of Glutathione. Chem. - Eur. J. 2016, 22 (44), 15937– 15944, DOI: 10.1002/chem.201603366
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The Copper(II)-Catalyzed Oxidation of Glutathione
Ngamchuea, Kamonwad; Batchelor-McAuley, Christopher; Compton, Richard G.
Chemistry - A European Journal (2016), 22 (44), 15937-15944CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
The kinetics and mechanisms of the copper(II)-catalyzed GSH (glutathione) oxidn. are examd. in the light of its biol. importance and in the use of blood and/or saliva samples for GSH monitoring. The rates of the free thiol consumption were measured spectrophotometrically by reaction with DTNB (5,5'-dithiobis-(2-nitrobenzoic acid)), showing that GSH is not auto-oxidized by oxygen in the absence of a catalyst. In the presence of Cu2+, reactions with two timescales were obsd. The first step (short timescale) involves the fast formation of a copper-glutathione complex by the cysteine thiol. The second step (longer timescale) is the overall oxidn. of GSH to GSSG (glutathione disulfide) catalyzed by copper(II). When the initial concns. of GSH are at least threefold in excess of Cu2+, the rate law is deduced to be -d[thiol]/dt=k[copper-glutathione complex][O2]0.5[H2O2]-0.5. The 0.5th reaction order with respect to O2 reveals a pre-equil. prior to the rate-detg. step of the GSSG formation. In contrast to [Cu2+] and [O2], the rate of the reactions decreases with increasing concns. of GSH. This inverse relationship is proposed to be a result of the competing formation of an inactive form of the copper-glutathione complex (binding to glutamic and/or glycine moieties).
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Gonzalez, P.; Vileno, B.; Bossak, K.; El Khoury, Y.; Hellwig, P.; Bal, W.; Hureau, C.; Faller, P. Cu(II) Binding to the Peptide Ala-His-His, a Chimera of the Canonical Cu(II)-Binding Motifs Xxx-His and Xxx-Zzz-His. Inorg. Chem. 2017, 56 (24), 14870, DOI: 10.1021/acs.inorgchem.7b01996
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Cu(II) Binding to the Peptide Ala-His-His, a Chimera of the Canonical Cu(II)-Binding Motifs Xxx-His and Xxx-Zzz-His
Gonzalez, Paulina; Vileno, Bertrand; Bossak, Karolina; El Khoury, Youssef; Hellwig, Petra; Bal, Wojciech; Hureau, Christelle; Faller, Peter
Inorganic Chemistry (2017), 56 (24), 14870-14879CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
Peptides and proteins with the N-terminal motifs NH2-Xxx-His and NH2-Xxx-Zzz-His form well established Cu(II)-complexes. The canonical peptides are Gly-His-Lys and Asp-Ala-His-Lys (from the wound healing factor and human serum albumin, resp.). Cu(II) is bound to NH2-Xxx-His via 3 nitrogens from the peptide and an external ligand in the equatorial plane (called 3N form here). In contrast, Cu(II) is bound to NH2-Xxx-Zzz-His via 4 nitrogens from the peptide in the equatorial plane (called 4N form here). These two motifs are not mutually exclusive, as the peptides with the sequence NH2-Xxx-His-His contain both of them. However, this chimera has never been really explored. In this work, we use a multispectroscopic approach to analyze the Cu(II)-binding to the chimeric peptide Ala-His-His (AHH). AHH is capable to form the 3N and 4N type complexes in a pH dependent manner. The 3N form predominates at pH ∼ 4-6.5 and the 4N form at ∼ pH 6.5-10. NMR expts. showed that at pH 8.5, where Cu(II) is almost exclusively bound in the 4N form, the Cu(II)-exchange between AHH or the amidated AHH-NH2 is fast, in comparison to the nonchimeric 4N form (AAH). Together the results show that the chimeric AHH can access both Cu(II) coordination types, that minor changes in the second (or further) coordination sphere can impact considerably the equil. between the forms and that Cu kinetic exchange is fast even when Cu-AHH is mainly in the 4N form.
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Gonzalez, P.; Bossak-Ahmad, K.; Vileno, B.; Wezynfeld, N. E.; El Khoury, Y.; Hellwig, P.; Hureau, C.; Bal, W.; Faller, P. Triggering Cu-Coordination Change in Cu(Ii)-Ala-His-His by External Ligands. Chem. Commun. 2019, 55 (56), 8110– 8113, DOI: 10.1039/C9CC03174J
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Triggering Cu-coordination change in Cu(II)-Ala-His-His by external ligands
Gonzalez, Paulina; Bossak-Ahmad, Karolina; Vileno, Bertrand; Wezynfeld, Nina E.; El Khoury, Youssef; Hellwig, Petra; Hureau, Christelle; Bal, Wojciech; Faller, Peter
Chemical Communications (Cambridge, United Kingdom) (2019), 55 (56), 8110-8113CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
Copper(II) forms well-known and stable complexes with peptides having histidine at position 2 (Xxx-His) or 3 (Xxx-Zzz-His). Their properties differ considerably due to the histidine positioning. Here we report that in the hybrid motif Xxx-His-His, the Cu(II)-complexes can be switched between the Xxx-His and the Xxx-Zzz-His coordination modes by addn. of external ligands.
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Hureau, C.; Eury, H.; Guillot, R.; Bijani, C.; Sayen, S.; Solari, P.-L.; Guillon, E.; Faller, P.; Dorlet, P. X-Ray and Solution Structures of CuIIGHK and CuIIDAHK Complexes: Influence on Their Redox Properties. Chem. - Eur. J. 2011, 17 (36), 10151– 10160, DOI: 10.1002/chem.201100751
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X-Ray and Solution Structures of CuIIGHK and CuIIDAHK Complexes: Influence on Their Redox Properties
Hureau, Christelle; Eury, Helene; Guillot, Regis; Bijani, Christian; Sayen, Stephanie; Solari, Pier-Lorenzo; Guillon, Emmanuel; Faller, Peter; Dorlet, Pierre
Chemistry - A European Journal (2011), 17 (36), 10151-10160, S10151/1-S10151/17CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
The Gly-His-Lys (GHK) peptide and the Asp-Ala-His-Lys (DAHK) sequences are naturally occurring high-affinity copper(II) chelators found in the blood plasma and are hence of biol. interest. A structural study of the copper complexes of these peptides was conducted in the solid state and in soln. by detg. their X-ray structures, and by using a large range of spectroscopies, including EPR and HYSCORE (hyperfine sub-level correlation), X-ray absorption and 1H and 13C NMR spectroscopy. The results indicate that the structures of [CuII(DAHK)] in the solid state and in soln. are similar and confirm the equatorial coordination sphere of NH2, two amidyl N and one imidazole N. Addnl., a water mol. is bound apically to CuII as revealed by the X-ray structure. As reported previously in the literature, [CuII(GHK)], which exhibits a dimeric structure in the solid state, forms a monomeric complex in soln. with three nitrogen ligands: NH2, amidyl and imidazole. The fourth equatorial site is occupied by a labile oxygen atom from a carboxylate ligand in the solid state. We probe that fourth position and study ternary complexes of [CuII(GHK)] with glycine or histidine. The CuII exchange reaction between different DAHK peptides is very slow, in contrast to [CuII(GHK)], in which the fast exchange was attributed to the presence of a [CuII(GHK)2] complex. The redox properties of [CuII(GHK)] and [CuII(DAHK)] were investigated by cyclic voltammetry and by measuring the ascorbate oxidn. in the presence of mol. oxygen. The measurements indicate that both CuII complexes are inert under moderate redox potentials. In contrast to [CuII(DAHK)], [CuII(GHK)] could be reduced to CuI around -0.62 V (vs. AgCl/Ag) with subsequent release of the Cu ion. These complete analyses of structure and redox activity of those complexes gave new insights with biol. impact and can serve as models for other more complicated CuII-peptide interactions.
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Atrián-Blasco, E.; Del Barrio, M.; Faller, P.; Hureau, C. Ascorbate Oxidation by Cu(Amyloid-â) Complexes: Determination of the Intrinsic Rate as a Function of Alterations in the Peptide Sequence Revealing Key Residues for Reactive Oxygen Species Production. Anal. Chem. 2018, 90 (9), 5909– 5915, DOI: 10.1021/acs.analchem.8b00740
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Ascorbate Oxidation by Cu(Amyloid-β) Complexes: Determination of the Intrinsic Rate as a Function of Alterations in the Peptide Sequence Revealing Key Residues for Reactive Oxygen Species Production
Atrian-Blasco, Elena; del Barrio, Melisa; Faller, Peter; Hureau, Christelle
Analytical Chemistry (Washington, DC, United States) (2018), 90 (9), 5909-5915CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
Along with aggregation of the amyloid-β (Aβ) peptide and subsequent deposit of amyloid plaques, oxidative stress is an important feature in Alzheimer's disease. Cu bound to Aβ is able to produce Reactive Oxygen Species (ROS) by the successive redns. of mol. dioxygen and the ROS such produced contribute to oxidative stress. In vitro, ROS prodn. parallels the ascorbate consumption, where ascorbate is the reductant that fuels the reactions. Because the affinity of Cu for Aβ is moderate compared to other biomols., the rate of ascorbate consumption is a combination of two contributions. The first one is due to peptide-unbound Cu and the second one to peptide-bound Cu complexes. In the present article, we aim at detg. the amts. of the second contribution in the global ascorbate consumption process. It is defined as the intrinsic rate of ascorbate oxidn., which math. corresponds to the rate at an infinite peptide to Cu ratio, i.e. without any contribution from peptide-unbound Cu. We show that for the wild-type Cu(Aβ) complex, this value equals 10% of the value obtained for peptide-unbound Cu and that this value is strongly dependent on peptide alterations. By examn. of the dependence of the intrinsic rate of ascorbate oxidn., followed by UV-Vis spectroscopy, for several altered peptides, we det. some of the key residues that influence ROS prodn.
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Atrián-Blasco, E.; Gonzalez, P.; Santoro, A.; Alies, B.; Faller, P.; Hureau, C. Cu and Zn Coordination to Amyloid Peptides: From Fascinating Chemistry to Debated Pathological Relevance. Coord. Chem. Rev. 2018, 371, 38– 55, DOI: 10.1016/j.ccr.2018.04.007
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Cu and Zn coordination to amyloid peptides: From fascinating chemistry to debated pathological relevance
Atrian-Blasco, Elena; Gonzalez, Paulina; Santoro, Alice; Alies, Bruno; Faller, Peter; Hureau, Christelle
Coordination Chemistry Reviews (2018), 371 (), 38-55CODEN: CCHRAM; ISSN:0010-8545. (Elsevier B.V.)
A review. Several diseases share misfolding of different peptides and proteins as a key feature for their development. This is the case of important neurodegenerative diseases such as Alzheimer's and Parkinson's diseases and type II diabetes mellitus. Furthermore, metal ions such as copper and zinc might play an important role upon interaction with amyloidogenic peptides and proteins, which could impact their aggregation and toxicity abilities. In this review, the different coordination modes proposed for copper and zinc with amyloid-β, α-synuclein and IAPP will be reviewed as well as their impact on the aggregation, and ROS prodn. in the case of copper. In addn., a special focus will be given to the mutations that affect metal binding and lead to familial cases of the diseases. Different modifications of the peptides that have been obsd. in vivo and could be relevant for the coordination of metal ions are also described.
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Katharina Zimmeter, Bertrand Vileno, Carlos Platas-Iglesias, Bharath Vinjamuri, Angélique Sour, Peter Faller. Derivatization of the Peptidic Xxx-Zzz-His Motif toward a Ligand with Attomolar CuII Affinity under Maintaining High Selectivity and Fast Redox Silencing. Inorganic Chemistry 2023, 62 (24) , 9429-9439. https://doi.org/10.1021/acs.inorgchem.3c00480
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Talia Ho, Soha Ahmadi, Kagan Kerman. Do glutathione and copper interact to modify Alzheimer's disease pathogenesis?. Free Radical Biology and Medicine 2022, 181 , 180-196. https://doi.org/10.1016/j.freeradbiomed.2022.01.025
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Abstract
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Figure 1
Figure 1. UV–vis spectra of the reaction of 0.315 mM Cu(II) ions with 1.75 mM GSH in the presence of 0.35 mM Aβ_4–16 in 20 mM ammonium acetate buffer, pH 7.4, carried out for 25–30 h at 25 °C under aerobic (A) and anaerobic (B) conditions. UV–vis spectrum of Cu(II)Aβ_4–16 showed by dashed line. The spectra were recorded in 10 min intervals. Insets show selected kinetic traces at 525 nm.
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Figure 2
Figure 2. UV–vis spectra of the reaction of 0.315 mM Cu(II) ions with 1.75 mM GSH in the presence of 0.35 mM Aβ_4–9 (A) and Aβ_12–16 (B) in 20 mM ammonium acetate buffer, pH 7.4, carried out for 22–24 h at 25 °C under aerobic conditions. The spectra were recorded in 10 min intervals. Insets show selected kinetic traces at 527 nm (A) and 524 nm (B).
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  Masters, Colin L.; Selkoe, Dennis J.
  Cold Spring Harbor Perspectives in Medicine (2012), 2 (6), a006262/1-a006262/24CODEN: CSHPFV; ISSN:2157-1422. (Cold Spring Harbor Laboratory Press)
  A review. Progressive cerebral deposition of the amyloid β-protein (Aβ) in brain regions serving memory and cognition is an invariant and defining feature of Alzheimer disease. A highly similar but less robust process accompanies brain aging in many nondemented humans, lower primates, and some other mammals. The discovery of Aβ as the subunit of the amyloid fibrils in meningocerebral blood vessels and parenchymal plaques has led to innumerable studies of its biochem. and potential cytotoxic properties. Here we will review the discovery of Aβ, numerous aspects of its complex biochem., and current attempts to understand how a range of Aβ assemblies, including sol. oligomers and insol. fibrils, may ppt. and promote neuronal and glial alterations that underlie the development of dementia. Although the role of Aβ as a key mol. factor in the etiol. of Alzheimer disease remains controversial, clin. trials of amyloid-lowering agents, reviewed elsewhere in this book, are poised to resolve the question of its pathogenic primacy.
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6. 6
  Zott, B.; Simon, M. M.; Hong, W.; Unger, F.; Chen-Engerer, H.-J.; Frosch, M. P.; Sakmann, B.; Walsh, D. M.; Konnerth, A. A Vicious Cycle of β Amyloid-Dependent Neuronal Hyperactivation. Science (Washington, DC, U. S.) 2019, 365 (6453), 559– 565, DOI: 10.1126/science.aay0198
  6
  A vicious cycle of β amyloid-dependent neuronal hyperactivation
  Zott, Benedikt; Simon, Manuel M.; Hong, Wei; Unger, Felix; Chen-Engerer, Hsing-Jung; Frosch, Matthew P.; Sakmann, Bert; Walsh, Dominic M.; Konnerth, Arthur
  Science (Washington, DC, United States) (2019), 365 (6453), 559-565CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
  Progressive accumulation of amyloid β (Aβ) in the brain is a defining feature of Alzheimer's disease (AD). At late stages of AD, pathol. Aβ accumulations cause neurodegeneration and cell death. However, neuronal dysfunction, consisting of an excessively increased activity in a fraction of brain neurons, already occurs in early stages of the disease. Zott et al. explored the cellular basis of this hyperactivity in mouse models of AD (see the Perspective by Selkoe). Aβ-mediated hyperactivation was linked to a defect in synaptic transmission exclusively in active neurons, with the most-active neurons having the highest risk of hyperactivation. Aβ-contg. brain exts. from human AD patients sustained this vicious cycle, underscoring the potential relevance of this pathol. mechanism in humans.
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7. 7
  Lewis, H.; Beher, D.; Cookson, N.; Oakley, A.; Piggott, M.; Morris, C. M.; Jaros, E.; Perry, R.; Ince, P.; Kenny, R. A.; Ballard, C. G.; Shearman, M. S.; Kalaria, R. N. Quantification of Alzheimer Pathology in Ageing and Dementia: Age-Related Accumulation of Amyloid-Beta(42) Peptide in Vascular Dementia. Neuropathol. Appl. Neurobiol. 2006, 32 (2), 103– 118, DOI: 10.1111/j.1365-2990.2006.00696.x
  7
  Quantification of Alzheimer pathology in ageing and dementia: age-related accumulation of amyloid-β(42) peptide in vascular dementia
  Lewis, H.; Beher, D.; Cookson, N.; Oakley, A.; Piggott, M.; Morris, C. M.; Jaros, E.; Perry, R.; Ince, P.; Kenny, R. A.; Ballard, C. G.; Shearman, M. S.; Kalaria, R. N.
  Neuropathology and Applied Neurobiology (2006), 32 (2), 103-118CODEN: NANEDL; ISSN:0305-1846. (Blackwell Publishing Ltd.)
  Clinicopathol. observations suggest there is considerable overlap between vascular dementia (VaD) and Alzheimer's disease (AD). We used immunochem. methods to compare quantities of amyloid-β (Aβ) peptides in post mortem brain samples from VaD. AD subjects and nondemented aging controls. Total Aβ peptides extd. from temporal and frontal cortices were quantified using a previously characterized sensitive homogenous time-resolved fluorescence (HTRF) assay. The HTRF assays and immunocapture mass spectrometric analyses revealed that the Aβ(42) species were by far the predominant form of extractable peptide compared with Aβ(40) peptide in VaD brains. The strong signal intensity for the peak representing Aβ(4-42) peptide confirmed that these N-terminally truncated species are relatively abundant. Abs. quantification by HTRF assay showed that the mean amt. of total Aβ(42) recovered from VaD samples was approx. 50% of that in AD, and twice that in the age-matched controls. Linear correlation anal. further revealed an increased accumulation with age of both Aβ peptides in brains of VaD subjects and controls. Interestingly, VaD patients surviving beyond 80 years of age exhibited comparable Aβ(42) concns. with those in AD in the temporal cortex. Our findings suggest that brain Aβ accumulates increasingly with age in VaD subjects more so than in elderly without cerebrovascular disease and support the notion that they acquire Alzheimer-like pathol. in older age.
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8. 8
  Portelius, E.; Bogdanovic, N.; Gustavsson, M. K.; Volkmann, I.; Brinkmalm, G.; Zetterberg, H.; Winblad, B.; Blennow, K. Mass Spectrometric Characterization of Brain Amyloid Beta Isoform Signatures in Familial and Sporadic Alzheimer’s Disease. Acta Neuropathol. 2010, 120 (2), 185– 193, DOI: 10.1007/s00401-010-0690-1
  8
  Mass spectrometric characterization of brain amyloid beta isoform signatures in familial and sporadic Alzheimer's disease
  Portelius, Erik; Bogdanovic, Nenad; Gustavsson, Mikael K.; Volkmann, Inga; Brinkmalm, Gunnar; Zetterberg, Henrik; Winblad, Bengt; Blennow, Kaj
  Acta Neuropathologica (2010), 120 (2), 185-193CODEN: ANPTAL; ISSN:0001-6322. (Springer)
  A proposed key event in the pathogenesis of Alzheimer's disease (AD) is the formation of neurotoxic amyloid β (Aβ) oligomers and amyloid plaques in specific brain regions that are affected by the disease. The main plaque component is the 42 amino acid isoform of Αβ (Aβ1-42), which is thought to initiate plaque formation and AD pathogenesis. Numerous isoforms of Aβ, e.g., Aβ1-42, Aβ1-40 and the 3-pyroglutamate derivate of Aβ3-42 (pGluAβ3-42), have been detected in the brains of sporadic AD (SAD) and familial AD (FAD) subjects. However, the relative importance of these isoforms in the pathogenesis of AD is not fully understood. Here, we report a detailed study using immunopptn. in combination with mass spectrometric anal. to det. the Aβ isoform pattern in the cerebellum, cortex and hippocampus in AD, including subjects with a mutation in the presenilin (M146V) or amyloid precursor protein (KM670/671NL) genes, SAD subjects and non-demented controls. We show that the dominating Aβ isoforms in the three different brain regions analyzed from control, SAD, and FAD are Aβ1-42, pGluAβ3-42, Aβ4-42 and Aβ1-40 of which Aβ1-42 and Aβ4-42 are the dominant isoforms in the hippocampus and the cortex in all groups analyzed, controls included. No prominent differences in Aβ isoform patterns between FAD and SAD patients were seen, underscoring the similarity in the amyloid pathol. of these two disease entities.
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9. 9
  Alies, B.; Renaglia, E.; Rózga, M.; Bal, W.; Faller, P.; Hureau, C. Cu(II) Affinity for the Alzheimer’s Peptide: Tyrosine Fluorescence Studies Revisited. Anal. Chem. 2013, 85 (3), 1501– 1508, DOI: 10.1021/ac302629u
  9
  Cu(II) Affinity for the Alzheimer's Peptide: Tyrosine Fluorescence Studies Revisited
  Alies, Bruno; Renaglia, Emelyne; Rozga, Malgorzata; Bal, Wojciech; Faller, Peter; Hureau, Christelle
  Analytical Chemistry (Washington, DC, United States) (2013), 85 (3), 1501-1508CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
  Copper(II) binding to the amyloid-β peptide has been proposed to be a key event in the cascade leading to Alzheimer's disease. As a direct consequence, the strength of the Cu(II) to Aβ interaction, i.e., the Cu(II) affinity of Aβ, is a very important parameter to det. Because Aβ peptide contain one Tyr fluorophore in its sequence and because Cu(II) does quench Tyr fluorescence, fluorescence measurements appear to be a straightforward way to obtain this parameter. However, this proved to be wrong, mainly because of data misinterpretation in some previous studies that lead to a conflicting situation. In the present paper, we have investigated in details a large set of fluorescence data that were analyzed with a new method taking into account the presence of two Cu(II) sites and the inner-filter effect. This leads to reinterpretation of the published data and to the detn. of a unified affinity value in the 1010 M-1 range.
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10. 10
  Young, T. R.; Kirchner, A.; Wedd, A. G.; Xiao, Z. An Integrated Study of the Affinities of the Aβ16 Peptide for Cu(I) and Cu(II): Implications for the Catalytic Production of Reactive Oxygen Species. Metallomics 2014, 6 (3), 505– 517, DOI: 10.1039/C4MT00001C
  10
  An integrated study of the affinities of the Aβ16 peptide for Cu(i) and Cu(ii): implications for the catalytic production of reactive oxygen species
  Young, Tessa R.; Kirchner, Angie; Wedd, Anthony G.; Xiao, Zhiguang
  Metallomics (2014), 6 (3), 505-517CODEN: METAJS; ISSN:1756-591X. (Royal Society of Chemistry)
  A new fluorescent probe Aβ16wwa based upon the Aβ16 peptide has been developed with two orders of magnitude greater fluorescence intensity for sensitive detection of interactions with Cu(ii). In combination with the Cu(i) probe Ferene S, it is confirmed that the Aβ16 peptide binds either Cu(i) or Cu(ii) with comparable affinities at pH 7.4 (log KID = -10.4; log KIID = -10.0). It follows from this property that the Cu-Aβ16 complex is a robust if slow catalyst for the aerial oxidn. of ascorbate with H2O2 as primary product (initial rate, ∼0.63 min-1 for Cu-Aβ16 vs. >2.5 min-1 for Cuaq2+). An integrated study of variants of this peptide identifies the major ligands and binding modes involved in its copper complexes in soln. The dependence of KID upon pH is consistent with a two-coordinate Cu(i) site in which dynamic processes exchange Cu(i) between the three available pairs of imidazole sidechains provided by His6, His13 and His14. The N-terminal amine is not involved in Cu(i) binding but is a key ligand for Cu(ii). Acetylation of the N-terminus alters the redox thermodn. gradient for the Cu center and suppresses its catalytic activity considerably. The data indicate the presence of dynamic processes that exchange Cu(ii) between the three His ligands and backbone amide at physiol. pH. His6 is identified as a key ligand for catalysis as its presence minimizes the pre-organization energy required for interchange of the two copper redox sites. These new thermodn. data strengthen structural interpretations for the Cu-Aβ complexes and provide valuable insights into the mol. mechanism by which copper chem. may induce oxidative stress in Alzheimer's disease.
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11. 11
  Conte-Daban, A.; Borghesani, V.; Sayen, S.; Guillon, E.; Journaux, Y.; Gontard, G.; Lisnard, L.; Hureau, C. Link between Affinity and Cu(II) Binding Sites to Amyloid-β Peptides Evaluated by a New Water-Soluble UV-Visible Ratiometric Dye with a Moderate Cu(II) Affinity. Anal. Chem. 2017, 89 (3), 2155– 2162, DOI: 10.1021/acs.analchem.6b04979
  11
  Link between Affinity and Cu(II) Binding Sites to Amyloid-β Peptides Evaluated by a New Water-Soluble UV-Visible Ratiometric Dye with a Moderate Cu(II) Affinity
  Conte-Daban, Amandine; Borghesani, Valentina; Sayen, Stephanie; Guillon, Emmanuel; Journaux, Yves; Gontard, Geoffrey; Lisnard, Laurent; Hureau, Christelle
  Analytical Chemistry (Washington, DC, United States) (2017), 89 (3), 2155-2162CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
  Being able to easily det. the Cu(II) affinity for biomols. of moderate affinity is important. Such biomols. include amyloidogenic peptides, such as the known amyloid-β peptide involved in Alzheimer's disease. Here, the authors report the synthesis of a new water-sol. ratiometric Cu(II) dye with a moderate affinity (109 M-1 at pH 7.1) and the characterizations of the Cu(II) corresponding complex by x-ray crystallog., EPR, and XAS spectroscopic methods. UV-visible competition was performed on the Aβ peptide as well as on a wide series of modified peptides, leading to an affinity value of 1.6 × 109 M-1 at pH 7.1 for the Aβ peptide and to a coordination model for the Cu(II) site within the Aβ peptide that agrees with the one mostly accepted currently.
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12. 12
  Cheignon, C.; Jones, M.; Atrián-Blasco, E.; Kieffer, I.; Faller, P.; Collin, F.; Hureau, C. Identification of Key Structural Features of the Elusive Cu–Aβ Complex That Generates ROS in Alzheimer’s Disease. Chem. Sci. 2017, 8 (7), 5107– 5118, DOI: 10.1039/C7SC00809K
  12
  Identification of key structural features of the elusive Cu-Aβ complex that generates ROS in Alzheimer's disease
  Cheignon, Clemence; Jones, Megan; Atrian-Blasco, Elena; Kieffer, Isabelle; Faller, Peter; Collin, Fabrice; Hureau, Christelle
  Chemical Science (2017), 8 (7), 5107-5118CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
  Oxidative stress is linked to the etiol. of Alzheimer's disease (AD), the most common cause of dementia in the elderly. Redox active metal ions such as copper catalyze the prodn. of Reactive Oxygen Species (ROS) when bound to the amyloid-β (Aβ) peptide encountered in AD. We propose that this reaction proceeds through a low-populated Cu-Aβ state, denoted the "catalytic in-between state" (CIBS), which is in equil. with the resting state (RS) of both Cu(I)-Aβ and Cu(II)-Aβ. The nature of this CIBS is investigated in the present work. We report the use of complementary spectroscopic methods (X-ray absorption spectroscopy, EPR and NMR) to characterize the binding of Cu to a wide series of modified peptides in the RS. ROS prodn. by the resulting Cu-peptide complexes was evaluated using fluorescence and UV-vis based methods and led to the identification of the amino acid residues involved in the Cu-Aβ CIBS species. In addn., a possible mechanism by which the ROS are produced is also proposed. These two main results are expected to affect the current vision of the ROS prodn. mechanism by Cu-Aβ but also in other diseases involving amyloidogenic peptides with weakly structured copper binding sites.
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13. 13
  Cheignon, C.; Faller, P.; Testemale, D.; Hureau, C.; Collin, F. Metal-Catalyzed Oxidation of Aβ and the Resulting Reorganization of Cu Binding Sites Promote ROS Production. Metallomics 2016, 8 (10), 1081– 1089, DOI: 10.1039/C6MT00150E
  13
  Metal-catalyzed oxidation of Aβ and the resulting reorganization of Cu binding sites promote ROS production
  Cheignon, Clemence; Faller, Peter; Testemale, Denis; Hureau, Christelle; Collin, Fabrice
  Metallomics (2016), 8 (10), 1081-1089CODEN: METAJS; ISSN:1756-591X. (Royal Society of Chemistry)
  In the context of Alzheimer's disease (AD), the prodn. of HO • by copper-amyloid beta (Aβ) in the presence of ascorbate is known to be deleterious for the Aβ peptide itself and also for the surrounding mols., thus establishing a direct link between AD and oxidative stress. The metal-catalyzed oxidn. (MCO) of Aβ primarily targets the residues involved in copper coordination during HO • prodn. In the present work, we demonstrate that the oxidative damage undergone by Aβ during MCO lead to a change in copper coordination, with enhanced catalytic properties that increases the rates of ascorbate consumption and HO • prodn., and the amt. of HO • released by the system. This phenomenon is obsd. after the peptide has been sufficiently oxidized.
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14. 14
  Cheignon, C.; Tomas, M.; Bonnefont-Rousselot, D.; Faller, P.; Hureau, C.; Collin, F. Oxidative Stress and the Amyloid Beta Peptide in Alzheimer’s Disease. Redox Biol. 2018, 14, 450– 464, DOI: 10.1016/j.redox.2017.10.014
  14
  Oxidative stress and the amyloid beta peptide in Alzheimer's disease
  Cheignon, C.; Tomas, M.; Bonnefont-Rousselot, D.; Faller, P.; Hureau, C.; Collin, F.
  Redox Biology (2018), 14 (), 450-464CODEN: RBEIB3; ISSN:2213-2317. (Elsevier B.V.)
  A review. Oxidative stress is known to play an important role in the pathogenesis of a no. of diseases. In particular, it is linked to the etiol. of Alzheimer's disease (AD), an age-related neurodegenerative disease and the most common cause of dementia in the elderly. Histopathol. hallmarks of AD are intracellular neurofibrillary tangles and extracellular formation of senile plaques composed of the amyloid-beta peptide (Aβ) in aggregated form along with metal-ions such as copper, iron or zinc. Redox active metal ions, as for example copper, can catalyze the prodn. of Reactive Oxygen Species (ROS) when bound to the amyloid-β (Aβ). The ROS thus produced, in particular the hydroxyl radical which is the most reactive one, may contribute to oxidative damage on both the Aβ peptide itself and on surrounding mol. (proteins, lipids, ...). This review highlights the existing link between oxidative stress and AD, and the consequences towards the Aβ peptide and surrounding mols. in terms of oxidative damage. In addn., the implication of metal ions in AD, their interaction with the Aβ peptide and redox properties leading to ROS prodn. are discussed, along with both in vitro and in vivo oxidn. of the Aβ peptide, at the mol. level.
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15. 15
  Mital, M.; Wezynfeld, N. E.; Frączyk, T.; Wiloch, M. Z.; Wawrzyniak, U. E.; Bonna, A.; Tumpach, C.; Barnham, K. J.; Haigh, C. L.; Bal, W.; Drew, S. C. A Functional Role for Aβ in Metal Homeostasis? N-Truncation and High-Affinity Copper Binding. Angew. Chem., Int. Ed. 2015, 54 (36), 10460– 10464, DOI: 10.1002/anie.201502644
  15
  A Functional Role for Aβ in Metal Homeostasis? N-Truncation and High-Affinity Copper Binding
  Mital, Mariusz; Wezynfeld, Nina E.; Fraczyk, Tomasz; Wiloch, Magdalena Z.; Wawrzyniak, Urszula E.; Bonna, Arkadiusz; Tumpach, Carolin; Barnham, Kevin J.; Haigh, Cathryn L.; Bal, Wojciech; Drew, Simon C.
  Angewandte Chemie, International Edition (2015), 54 (36), 10460-10464CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Accumulation of the β-amyloid (Aβ) peptide in extracellular senile plaques rich in copper and zinc is a defining pathol. feature of Alzheimer's disease (AD). The Aβ1-x (x=16/28/40/42) peptides have been the primary focus of CuII binding studies for more than 15 years; however, the N-truncated Aβ4-42 peptide is a major Aβ isoform detected in both healthy and diseased brains, and it contains a novel N-terminal FRH sequence. Proteins with His at the third position are known to bind CuII avidly, with conditional log K values at pH 7.4 in the range of 11.0-14.6, which is much higher than that detd. for Aβ1-x peptides. By using Aβ4-16 as a model, it was demonstrated that its FRH sequence stoichiometrically binds CuII with a conditional Kd value of 3×10-14 M at pH 7.4, and that both Aβ4-16 and Aβ4-42 possess negligible redox activity. Combined with the predominance of Aβ4-42 in the brain, our results suggest a physiol. role for this isoform in metal homeostasis within the central nervous system.
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16. 16
  Harford, C.; Sarkar, B. Amino Terminal Cu(II)- and Ni(II)-Binding (ATCUN) Motif of Proteins and Peptides: Metal Binding, DNA Cleavage, and Other Properties. Acc. Chem. Res. 1997, 30 (3), 123– 130, DOI: 10.1021/ar9501535
  16
  Amino Terminal Cu(II)- and Ni(II)-Binding Motif of Proteins and Peptides: Metal Binding, DNA Cleavage, and Other Properties
  Harford, Catherine; Sarkar, Bibudhendra
  Accounts of Chemical Research (1997), 30 (3), 123-130CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
  A review, with 74 refs., on the amino terminal Cu(II)- and Ni(II)-binding ATCUN (motif). The ATCUN motif is a structural feature which can be defined as being present in a protein or peptide which has (1) a free NH2-terminus, (2) a histidine residue in the third position, and (3) two intervening peptide nitrogens. Topics include the origin of the ATCUN motif from the early characterization of the metal-binding properties within albumins, mol. design of the ATCUN motif, DNA cleavage properties of the ATCUN motif, use of the motif in protein design for the specific DNA cleavage, and prediction of naturally occurring proteins with the ATCUN motif.
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17. 17
  Stefaniak, E.; Bal, W. Binding Properties of N-Truncated Aβ Peptides: In Search of Biological Function. Inorg. Chem. 2019, 58 (20), 13561– 13577, DOI: 10.1021/acs.inorgchem.9b01399
  17
  CuII binding properties of N-truncated Aβ peptides: In search of biological function
  Stefaniak, Ewelina; Bal, Wojciech
  Inorganic Chemistry (2019), 58 (20), 13561-13577CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
  A review. As life expectancy increases, the no. of people affected by progressive and irreversible dementia, Alzheimer's Disease (AD), is predicted to grow. No drug designs seem to be working in humans, apparently because the origins of AD have not been identified. Invoking amyloid cascade, metal ions, and ROS prodn. hypothesis of AD, herein we share our point of view on Cu(II) binding properties of Aβ4-x, the most prevalent N-truncated Aβ peptide, currently known as the main constituent of amyloid plaques. The capability of Aβ4-x to rapidly take over copper from previously tested Aβ1-x peptides and form highly stable complexes, redox unreactive and resistant to copper exchange reactions, prompted us to propose physiol. roles for these peptides. We discuss the new findings on the reactivity of Cu(II)Aβ4-x with coexisting biomols. in the context of synaptic cleft; we suggest that the role of Aβ4-x peptides is to quench Cu(II) toxicity in the brain and maintain neurotransmission.
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18. 18
  Hopt, A.; Korte, S.; Fink, H.; Panne, U.; Niessner, R.; Jahn, R.; Kretzschmar, H.; Herms, J. Methods for Studying Synaptosomal Copper Release. J. Neurosci. Methods 2003, 128 (1), 159– 172, DOI: 10.1016/S0165-0270(03)00173-0
  18
  Methods for studying synaptosomal copper release
  Hopt, Alexander; Korte, Stefan; Fink, Herbert; Panne, Ulrich; Niessner, Reinhard; Jahn, Reinhard; Kretzschmar, Hans; Herms, Jochen
  Journal of Neuroscience Methods (2003), 128 (1,2), 159-172CODEN: JNMEDT; ISSN:0165-0270. (Elsevier Science B.V.)
  Cu is thought to play an important role in the pathogenesis of several neurodegenerative diseases, such as Wilson's, Alzheimer's, and probably in prion protein diseases like Creutzfeldt-Jakob's disease. Until now, no method existed to det. the concn. of this cation in vivo. Here, we present two possible approaches combined with a crit. comparison of the results. The successful use of fluorescent ligands for the detn. of Ca2+-concns. in recent years encouraged us to seek a fluorophore which specifically reacts to Cu2+ and to characterize it for our purposes. We found that the emission of TSPP (tetrakis-(4-sulfophenyl)porphine) at an emission wavelength of 645 nm is in vitro highly specific to Cu2+ (apparent dissocn. const. Kd=0.43±0.07 μM at pH 7.4). It does not react with the most common divalent cations in the brain, Ca2+ and Mg2+, unlike most of the other dyes examd. In addn., Zn2+ quenches TSPP fluorescence at a different emission wavelength (605 nm) with a Kd of 50±2.5 μM (pH 7.0). With these findings, we applied the measurement of Cu with TSPP to a biol. system, showing for the first time in vivo that there is release of copper by synaptosomes upon depolarization. Our findings were validated with a completely independent anal. approach based on ICP-MS (inductively-coupled-plasma mass-spectrometry).
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19. 19
  Shibata, M.; Yamada, S.; Kumar, S. R.; Calero, M.; Bading, J.; Frangione, B.; Holtzman, D. M.; Miller, C. A.; Strickland, D. K.; Ghiso, J.; Zlokovic, B. V. Clearance of Alzheimer’s Amyloid-Ss(1–40) Peptide from Brain by LDL Receptor-Related Protein-1 at the Blood-Brain Barrier. J. Clin. Invest. 2000, 106 (12), 1489– 1499, DOI: 10.1172/JCI10498
  19
  Clearance of Alzheimer's amyloid-β1-40 peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier
  Shibata, Masayoshi; Yamada, Shinya; Kumar, S. Ram; Calero, Miguel; Bading, James; Frangione, Blas; Holtzman, David M.; Miller, Carol A.; Strickland, Dudley K.; Ghiso, Jorge; Zlokovic, Berislav V.
  Journal of Clinical Investigation (2000), 106 (12), 1489-1499CODEN: JCINAO; ISSN:0021-9738. (American Society for Clinical Investigation)
  Elimination of amyloid-β peptide (Aβ) from the brain is poorly understood. After intracerebral microinjections in young mice, 125I-Aβ1-40 was rapidly removed from the brain (t1/2 ≤ 25 min), mainly by vascular transport across the blood-brain barrier (BBB). The efflux transport system for Aβ1-40 at the BBB was half satd. at 15.3 nM, and the maximal transport capacity was reached between 70 nM and 100 nM. Aβ1-40 clearance was substantially inhibited by the receptor-assocd. protein, and by antibodies against LDL receptor-related protein-1 (LRP-1) and α2-macroglobulin (α2M). As compared to adult wild-type mice, clearance was significantly reduced in young and old apolipoprotein E (apoE) knockout mice, and in old wild-type mice. There was no evidence that Aβ was metabolized in brain interstitial fluid and degraded to smaller peptide fragments and amino acids before its transport across the BBB into the circulation. LRP-1, although abundant in brain microvessels in young mice, was downregulated in older animals, and this downregulation correlated with regional Aβ accumulation in brains of Alzheimer's disease (AD) patients. The authors conclude that the BBB removes Aβ from the brain largely via age-dependent, LRP-1-mediated transport that is influenced by α2M and/or apoE, and may be impaired in AD.
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20. 20
  Deane, R.; Du Yan, S.; Submamaryan, R. K.; LaRue, B.; Jovanovic, S.; Hogg, E.; Welch, D.; Manness, L.; Lin, C.; Yu, J.; Zhu, H.; Ghiso, J.; Frangione, B.; Stern, A.; Schmidt, A. M.; Armstrong, D. L.; Arnold, B.; Liliensiek, B.; Nawroth, P.; Hofman, F.; Kindy, M.; Stern, D.; Zlokovic, B. RAGE Mediates Amyloid-β Peptide Transport across the Blood-Brain Barrier and Accumulation in Brain. Nat. Med. 2003, 9 (7), 907– 913, DOI: 10.1038/nm890
  20
  RAGE mediates amyloid-β peptide transport across the blood-brain barrier and accumulation in brain
  Deane, Rashid; Yan, Shi Du; Submamaryan, Ram Kumar; LaRue, Barbara; Jovanovic, Suzana; Hogg, Elizabeth; Welch, Deborah; Manness, Lawrence; Lin, Chang; Yu, Jin; Zhu, Hong; Ghiso, Jorge; Frangione, Blas; Stern, Alan; Schmidt, Ann Marie; Armstrong, Don L.; Arnold, Bernd; Liliensiek, Birgit; Nawroth, Peter; Hofman, Florence; Kindy, Mark; Stern, David; Zlokovic, Berislav
  Nature Medicine (New York, NY, United States) (2003), 9 (7), 907-913CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)
  Amyloid-β peptide (Aβ) interacts with the vasculature to influence Aβ levels in the brain and cerebral blood flow, providing a means of amplifying the Aβ-induced cellular stress underlying neuronal dysfunction and dementia. Systemic Aβ infusion and studies in genetically manipulated mice show that Aβ interaction with receptor for advanced glycation end products (RAGE)-bearing cells in the vessel wall results in transport of Aβ across the blood-brain barrier (BBB) and expression of proinflammatory cytokines and endothelin-1 (ET-1), the latter mediating Aβ-induced vasoconstriction. Inhibition of RAGE-ligand interaction suppresses accumulation of Aβ in brain parenchyma in a mouse transgenic model. These findings suggest that vascular RAGE is a target for inhibiting pathogenic consequences of Aβ-vascular interactions, including development of cerebral amyloidosis.
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21. 21
  Paroni, G.; Bisceglia, P.; Seripa, D. Understanding the Amyloid Hypothesis in Alzheimer’s Disease. J. Alzheimer's Dis. 2019, 68 (2), 493– 510, DOI: 10.3233/JAD-180802
  21
  Understanding the Amyloid Hypothesis in Alzheimer's Disease
  Paroni, Giulia; Bisceglia, Paola; Seripa, Davide; Solfrizzi, Vincenzo
  Journal of Alzheimer's Disease (2019), 68 (2), 493-510CODEN: JADIF9; ISSN:1387-2877. (IOS Press)
  A review. The amyloid hypothesis (AH) is still the most accepted model to explain the pathogenesis of inherited Alzheimer's disease (IAD). However, despite the neuropathol. overlapping with the non-inherited form (NIAD), AH waver in explaining NIAD. Thus, 30 years after its first statement several questions are still open, mainly regarding the role of amyloid plaques (AP) and apolipoprotein E (APOE). Accordingly, a pathogenetic model including the role of AP and APOE unifying IAD and NIAD pathogenesis is still missing. In the present understanding of the AH, we suggested that amyloid-β (Aβ) peptides prodn. and AP formation is a physiol. aging process resulting from a systemic age-related decrease in the efficiency of the proteins catabolism/clearance machinery. In this pathogenetic model Aβ peptides act as neurotoxic mols., but only above a crit. concn. [Aβ]c. A threshold mechanism triggers IAD/NIAD onset only when [Aβ]≥[Aβ]c. In this process, APOE modifies [Aβ]c threshold in an isoform-specific way. Consequently, all factors influencing Aβ anabolism, such as amyloid beta precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) gene mutations, and/or Aβ catabolism/clearance could contribute to exceed the threshold [Aβ]c, being characteristic of each individual. In this model, AP formation does not depend on [Aβ]c. The present interpretation of the AH, unifying the pathogenetic theories for IAD and NIAD, will explain why AP and APOE4 may be obsd. in healthy aging and why they are not the cause of AD. It is clear that further studies are needed to confirm our pathogenetic model. Nevertheless, our suggestion may be useful to better understand the pathogenesis of AD.
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22. 22
  Kanemitsu, H.; Tomiyama, T.; Mori, H. Human Neprilysin Is Capable of Degrading Amyloid β Peptide Not Only in the Monomeric Form but Also the Pathological Oligomeric Form. Neurosci. Lett. 2003, 350 (2), 113– 116, DOI: 10.1016/S0304-3940(03)00898-X
  22
  Human neprilysin is capable of degrading amyloid β peptide not only in the monomeric form but also the pathological oligomeric form
  Kanemitsu, Hyoe; Tomiyama, Takami; Mori, Hiroshi
  Neuroscience Letters (2003), 350 (2), 113-116CODEN: NELED5; ISSN:0304-3940. (Elsevier Science Ltd.)
  Amyloid β-peptide (Aβ) is widely believed to play a central role in Alzheimer's disease (AD). Coordinate regulation of cerebral Aβ level is important in the pathogenesis of AD since either increased prodn. of Aβ from amyloid precursor protein or decreased degrdn. causes elevated levels of Aβ, leading to accumulation of cerebral plaque formation or amyloid angiopathy. Here the authors studied neprilysin, a putative proteolytic enzyme for Aβ, and found that it degraded not only monomeric but also oligomeric forms of Aβ1-40. Moreover, neprilysin was found to be capable of degrdn. of the oligomeric form of Aβ1-42, a significant Aβ species in early pathogenesis. Neprilysin to decrease cerebral Aβ is suggested to be inevitable factor as a vital therapeutic target.
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23. 23
  Oefner, C.; Roques, B. P.; Fournie-Zaluski, M.-C.; Dale, G. E. Structural Analysis of Neprilysin with Various Specific and Potent Inhibitors. Acta Crystallogr., Sect. D: Biol. Crystallogr. 2004, 60 (2), 392– 396, DOI: 10.1107/S0907444903027410
  23
  Structural analysis of neprilysin with various specific and potent inhibitors
  Oefner, Christian; Roques, Bernard P.; Fournie-Zaluski, Marie Claude; Dale, Glenn E.
  Acta Crystallographica, Section D: Biological Crystallography (2004), D60 (2), 392-396CODEN: ABCRE6; ISSN:0907-4449. (Blackwell Publishing Ltd.)
  Neutral endopeptidase (NEP) is the major enzyme involved in the metabolic inactivation of a no. of bioactive peptides including the enkephalins, substance P, endothelin, bradykinin, and atrial natriuretic factor. Owing to the physiol. importance of NEP in the modulation of nociceptive and pressor responses, there is considerable interest in inhibitors of this enzyme as novel analgesics and antihypertensive agents. Here, the crystal structures of the sol. extracellular domain of human NEP (residues 52-749) complexed with various potent and competitive inhibitors are described. The structures unambiguously reveal the binding mode of the different zinc-chelating groups and the subsite specificity of the enzyme.
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24. 24
  Mital, M.; Bal, W.; Frączyk, T.; Drew, S. C. Interplay between Copper, Neprilysin, and N-Truncation of β-Amyloid. Inorg. Chem. 2018, 57 (11), 6193– 6197, DOI: 10.1021/acs.inorgchem.8b00391
  24
  Interplay between Copper, Neprilysin, and N-Truncation of β-Amyloid
  Mital, Mariusz; Bal, Wojciech; Fraczyk, Tomasz; Drew, Simon C.
  Inorganic Chemistry (2018), 57 (11), 6193-6197CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
  Sporadic Alzheimer's disease (AD) is assocd. with an inefficient clearance of the β-amyloid (Aβ) peptide from the central nervous system. Protein levels and activity of the Zn2+-dependent endopeptidase, neprilysin (NEP), inversely correlate with brain Aβ levels during ageing and in AD. The present study considered the ability of Cu2+ ions to inhibit human recombinant NEP and the role for NEP in generation of N-truncated Aβ fragments with high-affinity Cu2+ binding motifs that could prevent this inhibition. Cu2+ noncompetitively inhibited NEP (Ki = 1.0 μM) and activity could not be restored by addn. of excess Zn2+, which also leads to NEP inhibition (Ki = 20 μM). Proteolysis of Aβ yielded the sol., non-amyloidogenic Aβ4-9 fragment that bound Cu2+ with femtomolar affinity at pH 7.4. This provided Aβ4-9 with the potential to act as a Cu2+ carrier and to mediate its own prodn. by preventing NEP inhibition. Inhibition by high Zn2+ concns. further suggested a mechanism for modulating NEP activity, Aβ4-9 prodn., and Cu2+ homeostasis.
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25. 25
  Bossak-Ahmad, K.; Mital, M.; Płonka, D.; Drew, S. C.; Bal, W. Oligopeptides Generated by Neprilysin Degradation of β-Amyloid Have the Highest Cu(II) Affinity in the Whole Aβ Family. Inorg. Chem. 2019, 58 (1), 932– 943, DOI: 10.1021/acs.inorgchem.8b03051
  25
  Oligopeptides generated by neprilysin degradation of β-amyloid have the highest Cu(II) affinity in the whole Aβ Family
  Bossak-Ahmad, Karolina; Mital, Mariusz; Plonka, Dawid; Drew, Simon C.; Bal, Wojciech
  Inorganic Chemistry (2019), 58 (1), 932-943CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
  The catabolism of β-amyloid (Aβ) is carried out by numerous endopeptidases including neprilysin, which hydrolyzes peptide bonds preceding positions 4, 10, and 12 to yield Aβ4-9 and a minor Aβ12-x species. Alternative processing of the amyloid precursor protein by β-secretase also generates the Aβ11-x species. All these peptides contain a Xxx-Yyy-His sequence, also known as an ATCUN or NTS motif, making them strong chelators of Cu(II) ions. We synthesized the corresponding peptides, Phe-Arg-His-Asp-Ser-Gly-OH (Aβ4-9), Glu-Val-His-His-Gln-Lys-am (Aβ11-16), Val-His-His-Gln-Lys-am (Aβ12-16), and pGlu-Val-His-His-Gln-Lys-am (pAβ11-16), and investigated their Cu(II) binding properties using potentiometry, and UV-vis, CD, and ESR spectroscopies. We found that the three peptides with unmodified N-termini formed square-planar Cu(II) complexes at pH 7.4 with analogous geometries but significantly varied Kd values of 6.6 fM (Aβ4-9), 9.5 fM (Aβ12-16), and 1.8 pM (Aβ11-16). Cyclization of the N-terminal Glu11 residue to the pyroglutamate species pAβ11-16 dramatically reduced the affinity (5.8 nM). The Cu(II) affinities of Aβ4-9 and Aβ12-16 are the highest among the Cu(II) complexes of Aβ peptides. Using fluorescence spectroscopy, we demonstrated that the Cu(II) exchange between the Phe-Arg-His and Val-His-His motifs is very slow, on the order of days. These results are discussed in terms of the relevance of Aβ4-9, a major Cu(II) binding Aβ fragment generated by neprilysin, as a possible Cu(II) carrier in the brain.
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26. 26
  Deane, R.; Bell, R. D.; Sagare, A.; Zlokovic, B. V. Clearance of Amyloid-Beta Peptide across the Blood-Brain Barrier: Implication for Therapies in Alzheimer’s Disease. CNS Neurol. Disord.: Drug Targets 2009, 8 (1), 16– 30, DOI: 10.2174/187152709787601867
  26
  Clearance of amyloid-β peptide across the blood-brain barrier: implication for therapies in Alzheimer's disease
  Deane, R.; Bell, R. D.; Sagare, A.; Zlokovic, B. V.
  CNS & Neurological Disorders: Drug Targets (2009), 8 (1), 16-30CODEN: CNDDA3; ISSN:1871-5273. (Bentham Science Publishers Ltd.)
  A review. The main receptors for amyloid-beta peptide (Aβ) transport across the blood-brain barrier (BBB) from brain to blood and blood to brain are low-d. lipoprotein receptor related protein-1 (LRP1) and receptor for advanced glycation end products (RAGE), resp. In normal human plasma a sol. form of LRP1 (sLRP1) is a major endogenous brain Aβ 'sinker' that sequesters some 70 to 90 % of plasma Aβ peptides. In Alzheimer's disease (AD), the levels of sLRP1 and its capacity to bind Aβ are reduced which increases free Aβ fraction in plasma. This in turn may increase brain Aβ burden through decreased Aβ efflux and/or increased Aβ influx across the BBB. In Aβ immunotherapy, anti-Aβ antibody sequestration of plasma Aβ enhances the peripheral Aβ 'sink action'. However, in contrast to endogenous sLRP1 which does not penetrate the BBB, some anti-Aβ antibodies may slowly enter the brain which reduces the effectiveness of their sink action and may contribute to neuroinflammation and intracerebral hemorrhage. Anti-Aβ antibody/Aβ immune complexes are rapidly cleared from brain to blood via FcRn (neonatal Fc receptor) across the BBB. In a mouse model of AD, restoring plasma sLRP1 with recombinant LRP-IV cluster reduces brain Aβ burden and improves functional changes in cerebral blood flow (CBF) and behavioral responses, without causing neuroinflammation and/or hemorrhage. The C-terminal sequence of Aβ is required for its direct interaction with sLRP and LRP-IV cluster which is completely blocked by the receptor-assocd. protein (RAP) that does not directly bind Aβ. Therapies to increase LRP1 expression or reduce RAGE activity at the BBB and/or restore the peripheral Aβ 'sink' action, hold potential to reduce brain Aβ and inflammation, and improve CBF and functional recovery in AD models, and by extension in AD patients.
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27. 27
  Maher, P. The Effects of Stress and Aging on Glutathione Metabolism. Ageing Res. Rev. 2005, 4 (2), 288– 314, DOI: 10.1016/j.arr.2005.02.005
  27
  The effects of stress and aging on glutathione metabolism
  Maher, Pamela
  Ageing Research Reviews (2005), 4 (2), 288-314CODEN: ARRGAK; ISSN:1568-1637. (Elsevier B.V.)
  A review. Glutathione plays a crit. role in many biol. processes both directly as a co-factor in enzymic reactions and indirectly as the major thiol-disulfide redox buffer in mammalian cells. Glutathione also provides a crit. defense system for the protection of cells from many forms of stress. However, mild stress generally increases glutathione levels, often but not exclusively through effects on glutamate cysteine ligase, the rate-limiting enzyme for glutathione biosynthesis. This upregulation in glutathione provides protection from more severe stress and may be a crit. feature of preconditioning and tolerance. In contrast, during aging, glutathione levels appear to decline in a no. of tissues, thereby putting cells at increased risk of succumbing to stress. The evidence for such a decline is strongest in the brain where glutathione loss is implicated in both Parkinson's disease and in neuronal injury following stroke.
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28. 28
  Sies, H. Glutathione and Its Role in Cellular Functions. Free Radical Biol. Med. 1999, 27, 916, DOI: 10.1016/S0891-5849(99)00177-X
  28
  Glutathione and its role in cellular functions
  Sies, Helmut
  Free Radical Biology & Medicine (1999), 27 (9/10), 916-921CODEN: FRBMEH; ISSN:0891-5849. (Elsevier Science Inc.)
  A review, with ∼114 refs. Glutathione (GSH) is the major cellular thiol participating in cellular redox reactions and thioether formation. This article serves as introduction to the FRBM Forum on glutathione and emphasizes cellular functions: What is GSH. Where does it come from. Where does it go. What does it do. What is new and noteworthy. Research tools, historical remarks, and links to current trends.
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29. 29
  Hatori, Y.; Lutsenko, S. The Role of Copper Chaperone Atox1 in Coupling Redox Homeostasis to Intracellular Copper Distribution. Antioxidants 2016, 5 (3), 25, DOI: 10.3390/antiox5030025
  29
  The role of copper chaperone Atox1 in coupling redox homeostasis to intracellular copper distribution
  Hatori, Yuta; Lutsenko, Svetlana
  Antioxidants (2016), 5 (3), 25/1-25/16CODEN: ANTIGE; ISSN:2076-3921. (MDPI AG)
  A review. Human antioxidant protein 1 (Atox1) is a small cytosolic protein with an essential role in copper homeostasis. Atox1 functions as a copper carrier facilitating copper transfer to the secretory pathway. This process is required for activation of copper dependent enzymes involved in neurotransmitter biosynthesis, iron efflux, neovascularization, wound healing, and regulation of blood pressure. Recently, new cellular roles for Atox1 have emerged. Changing levels of Atox1 were shown to modulate response to cancer therapies, contribute to inflammatory response, and protect cells against various oxidative stresses. It has also become apparent that the activity of Atox1 is tightly linked to the cellular redox status. In this review, we summarize biochem. information related to a dual role of Atox1 as a copper chaperone and an antioxidant. We discuss how these two activities could be linked and contribute to establishing the intracellular copper balance and functional identity of cells during differentiation.
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30. 30
  Maryon, E. B.; Molloy, S. A.; Kaplan, J. H. Cellular Glutathione Plays a Key Role in Copper Uptake Mediated by Human Copper Transporter 1. Am. J. Physiol. Cell Physiol. 2013, 304 (8), C768– C779, DOI: 10.1152/ajpcell.00417.2012
  There is no corresponding record for this reference.
31. 31
  Bachhawat, A. K.; Thakur, A.; Kaur, J.; Zulkifli, M. Glutathione Transporters. Biochim. Biophys. Acta, Gen. Subj. 2013, 1830 (5), 3154– 3164, DOI: 10.1016/j.bbagen.2012.11.018
  31
  Glutathione transporters
  Bachhawat, Anand K.; Thakur, Anil; Kaur, Jaspreet; Zulkifli, M.
  Biochimica et Biophysica Acta, General Subjects (2013), 1830 (5), 3154-3164CODEN: BBGSB3; ISSN:0304-4165. (Elsevier B.V.)
  A review. Glutathione (I) is synthesized in the cytoplasm, but there is a requirement for I not only in the cytoplasm, but in the other organelles and the extracellular milieu. I is also imported into the cytoplasm. The transport of I across these different membranes in different systems have been biochem. demonstrated. However the mol. identity of the transporters has been established only in a few cases. Here, an attempt is made to present the current state of knowledge of I transporters from different organisms as well as different organelles. These include the most well-characterized transporters, the yeast high-affinity, high-specificity I transporters involved in import into the cytoplasm, and the mammalian MRP proteins involved in low affinity I efflux from the cytoplasm. Other I transporters that have been described either with direct or indirect evidences are also discussed. The mol. identity of a few I transporters has been unambiguously established, but there is a need to identify the transporters of other systems and organelles. There is a lack of direct evidence establishing transport by suggested transporters in many cases. Studies with the high affinity transporters have led to important structure-function insights. An understanding of I transporters is crit. to an understanding of redox homeostasis in living cells. By presenting the current state of understanding and gaps in knowledge, the authors hope to stimulate research in these fields.
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32. 32
  Santoro, A.; Ewa Wezynfeld, N.; Vašák, M.; Bal, W.; Faller, P. Cysteine and Glutathione Trigger the Cu-Zn Swap between Cu(II)-Amyloid-Β4–16 Peptide and Zn7-Metallothionein-3. Chem. Commun. 2017, 53 (85), 11634– 11637, DOI: 10.1039/C7CC06802F
  32
  Cysteine and glutathione trigger the Cu-Zn swap between Cu(II)-amyloid-β4-16 peptide and Zn7-metallothionein-3
  Santoro, Alice; Ewa Wezynfeld, Nina; Vasak, Milan; Bal, Wojciech; Faller, Peter
  Chemical Communications (Cambridge, United Kingdom) (2017), 53 (85), 11634-11637CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
  Cysteine and glutathione are able to reduce Cu(II) coordinated to the peptide amyloidβ4-16, and shuttle the resulting Cu(I) to partially replace Zn(II) in the protein Zn7-metallothionein-3 complex. The released Zn(II) in turn binds to amyloid-β4-16. Thus, cysteine and glutathione are modulators of Cu/Zn-distribution between metallothionein-3 and amyloid-β4-16.
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33. 33
  Morgan, M. T.; Nguyen, L. A. H.; Hancock, H. L.; Fahrni, C. J. Glutathione Limits Aquacopper(I) to Sub-Femtomolar Concentrations through Cooperative Assembly of a Tetranuclear Cluster. J. Biol. Chem. 2017, 292 (52), 21558– 21567, DOI: 10.1074/jbc.M117.817452
  33
  Glutathione limits aquacopper(I) to sub-femtomolar concentrations through cooperative assembly of a tetranuclear cluster
  Morgan, M. Thomas; Nguyen, Lily Anh H.; Hancock, Haylie L.; Fahrni, Christoph J.
  Journal of Biological Chemistry (2017), 292 (52), 21558-21567CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
  The tripeptide glutathione (GSH) is a crucial intracellular reductant and radical scavenger, but it may also coordinate the soft Cu(I) cation and thereby yield pro-oxidant species. The GSH-Cu(I) interaction is thus a key consideration for both redox and copper homeostasis in cells. However, even after nearly four decades of investigation, the nature and stability of the GSH-Cu(I) complexes formed under biol. relevant conditions remain controversial. Here, we revealed the unexpected predominance of a tetranuclear [Cu4(GS)6] cluster that is sufficiently stable to limit the effective free aquacopper(I) concn. to the sub-femtomolar regime. Combined spectrophotometric-potentiometric titrns. at biol. realistic GSH/Cu(I) ratios, enabled by our recently developed Cu(I) affinity stds. and corroborated by low-temp. phosphorescence studies, established cooperative assembly of [Cu4(GS)6] as the dominant species over a wide pH range, from 5.5 to 7.5. Our robust model for the glutathione-Cu(I) equil. system sets a firm upper limit on the thermodn. availability of intracellular copper that is 3 orders of magnitude lower than previously estd. Taking into account their ability to catalyze the prodn. of deleterious superoxide, the formation of Cu(I)-glutathione complexes might be avoided under normal physiol. conditions. The actual intracellular Cu(I) availability may thus be regulated a further 3 orders of magnitude below the GSH/Cu(I) affinity limit, consistent with the most recent affinity detns. of Cu(I) chaperones.
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34. 34
  Speisky, H.; Gómez, M.; Carrasco-Pozo, C.; Pastene, E.; Lopez-Alarcón, C.; Olea-Azar, C. Cu(I)–Glutathione Complex: A Potential Source of Superoxide Radicals Generation. Bioorg. Med. Chem. 2008, 16 (13), 6568– 6574, DOI: 10.1016/j.bmc.2008.05.026
  34
  Cu(I)-Glutathione complex: A potential source of superoxide radicals generation
  Speisky, Hernan; Gomez, Maritza; Carrasco-Pozo, Catalina; Pastene, Edgar; Lopez-Alarcon, Camilo; Olea-Azar, Claudio
  Bioorganic & Medicinal Chemistry (2008), 16 (13), 6568-6574CODEN: BMECEP; ISSN:0968-0896. (Elsevier Ltd.)
  Cu2+ ions and GSH mols. interact swiftly to form the complex Cu(I)-glutathione. We investigated the potential capacity of such complex to reduce mol. oxygen. The addn. of SOD to a soln. contg. Cu(I)-glutathione led to a sustained decline of the basal oxygen level. Such effect was partially reverted by the addn. of catalase. The complex was able to induce the redn. of cytochrome c and the oxidn. of dihydroethidium into 2-hydroxyethidium. Both effects were totally blocked by SOD. The ability of the complex to generate superoxide radicals was confirmed by EPR spin-trapping. Cu(I)-glutathione induces no oxidn. of fluorescein, a hydroxyl radical-sensitive probe. We conclude that in solns. contg. the complex, oxygen is continually reduced into superoxide, and that-in absence of interceptors-the latter radicals are quant. re-oxidized into mol. oxygen. We suggest that, by functioning as a continuous source of superoxide, the complex could potentially affect a broad range of susceptible biol. targets.
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35. 35
  Várnagy, K.; Sóvágó, I.; Kozłowski, H. Transition Metal Complexes of Amino Acids and Derivatives Containing Disulphide Bridges. Inorg. Chim. Acta 1988, 151 (2), 117– 123, DOI: 10.1016/S0020-1693(00)91891-7
  35
  Transition metal complexes of amino acids and derivatives containing disulfide bridges
  Varnagy, Katalin; Sovago, Imre; Kozlowski, Henryk
  Inorganica Chimica Acta (1988), 151 (2), 117-23CODEN: ICHAA3; ISSN:0020-1693.
  The interaction of Co(II), Ni(II), Cu(II), and Zn with D-penicillamine disulfide, oxidized glutathione, and L-cysteinyglycine disulfide were studied by using pH-metric, spectrophotometric, and ESR methods. D-Penicillamine disulfide forms binuclear complexes with all the metal ions studied. The formation of 1:1 complexes is characteristic of oxidized glutathione. L-Cysteinylglycine disulfide behaves like dipeptides, but the presence of 2 sep. peptide moieties also results in the formation of various binuclear complexes. Metal ion-disulfide binding was not obsd. in any case.
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36. 36
  Meloni, G.; Faller, P.; Vašák, M. Redox Silencing of Copper in Metal-Linked Neurodegenerative Disorders: Reaction of Zn7metallothionein-3 with Cu2+ Ions. J. Biol. Chem. 2007, 282 (22), 16068– 16078, DOI: 10.1074/jbc.M701357200
  36
  Redox Silencing of Copper in Metal-linked Neurodegenerative Disorders: Reaction of Zn7metallothionein-3 with Cu2+ ions
  Meloni, Gabriele; Faller, Peter; Vasak, Milan
  Journal of Biological Chemistry (2007), 282 (22), 16068-16078CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
  Dysregulation of copper and zinc homeostasis in the brain plays a crit. role in Alzheimer disease (AD). Copper binding to amyloid-β peptide (Aβ) is linked with the neurotoxicity of Aβ and free radical damage. Metallothionein-3 (MT-3) is a small cysteine- and metal-rich protein expressed in the brain and found down-regulated in AD. This protein occurs intra- and extracellularly, and it plays an important role in the metab. of zinc and copper. In cell cultures Zn7MT-3, by an unknown mechanism, protects neurons from the toxicity of Aβ. We have, therefore, used a range of complementary spectroscopic and biochem. methods to characterize the interaction of Zn7MT-3 with free Cu2+ ions. We show that Zn7MT-3 scavenges free Cu2+ ions through their redn. to Cu+ and binding to the protein. In this reaction thiolate ligands are oxidized to disulfides concomitant with Zn2+ release. The binding of the first four Cu2+ is cooperative forming a Cu(I)4-thiolate cluster in the N-terminal domain of Cu4,Zn4MT-3 together with two disulfides bonds. The Cu4-thiolate cluster exhibits an unusual stability toward air oxygen. The results of UV-visible, CD, and Cu(I) phosphorescence at 77 K suggest the existence of metal-metal interactions in this cluster. We have demonstrated that Zn7MT-3 in the presence of ascorbate completely quenches the copper-catalyzed hydroxyl radical (OH•) prodn. Thus, zinc-thiolate clusters in Zn7MT-3 can efficiently silence the redox-active free Cu2+ ions. The biol. implication of our studies as to the protective role of Zn7MT-3 from the Cu2+ toxicity in AD and other neurodegenerative disorders is discussed.
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37. 37
  Wezynfeld, N. E.; Stefaniak, E.; Stachucy, K.; Drozd, A.; Płonka, D.; Drew, S. C.; Krężel, A.; Bal, W. Resistance of Cu(Aβ4–16) to Copper Capture by Metallothionein-3 Supports a Function for the Aβ4–42 Peptide as a Synaptic CuIIScavenger. Angew. Chem., Int. Ed. 2016, 55 (29), 8235– 8238, DOI: 10.1002/anie.201511968
  37
  Resistance of Cu(Aβ4-16) to copper capture by metallothionein-3 supports a function for the Aβ4-42 peptide as a synaptic CuII scavenger
  Wezynfeld, Nina E.; Stefaniak, Ewelina; Stachucy, Kinga; Drozd, Agnieszka; Plonka, Dawid; Drew, Simon C.; Krezel, Artur; Bal, Wojciech
  Angewandte Chemie, International Edition (2016), 55 (29), 8235-8238CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Aβ4-42 is a major species of amyloid-β (Aβ) peptide in the brains of both healthy individuals and those affected by Alzheimer's disease. It has recently been demonstrated to bind Cu2+ with an affinity ∼3000-fold higher than the commonly studied Aβ1-42 and Aβ1-40 peptides, which are implicated in the pathogenesis of Alzheimer's disease. Metallothionein-3, a protein considered to orchestrate Cu2+ and Zn2+ metab. in the brain and provide antioxidant protection, was shown to ext. Cu2+ from Aβ1-40 when acting in its native Zn7MT-3 form. This reaction is assumed to underlie the neuroprotective effect of Zn7MT-3 against Aβ toxicity. Here, the authors used truncated model peptides Aβ1-16 and Aβ4-16 to demonstrate that the high-affinity Cu2+ complex of Aβ4-16 is resistant to Zn7MT-3 reactivity. This indicated that the analogous complex of the full-length peptide, Cu(Aβ4-42), will not yield Cu2+ to MT-3 in the brain, thus supporting the concept of a physiol. role for Aβ4-42 as a Cu2+ scavenger in the synaptic cleft.
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38. 38
  Santoro, A.; Wezynfeld, N.; Stefaniak, E.; Pomorski, A.; Płonka, D.; Krezel, A.; Bal, W.; Faller, P. Cu Transfer from Amyloid-Β4–16 to Metallothionein-3: The Role of Neurotransmitter Glutamate and Metallothionein-3 Zn(II)-Load States. Chem. Commun. 2018, 54, 12634– 12637, DOI: 10.1039/C8CC06221H
  38
  Cu transfer from amyloid-β4-16 to metallothionein-3: the role of the neurotransmitter glutamate and metallothionein-3 Zn(II)-load states
  Santoro, Alice; Wezynfeld, Nina Ewa; Stefaniak, Ewelina; Pomorski, Adam; Plonka, Dawid; Krezel, Artur; Bal, Wojciech; Faller, Peter
  Chemical Communications (Cambridge, United Kingdom) (2018), 54 (89), 12634-12637CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
  Copper transfer from Cu(II)amyloid-β4-16 to human Zn7-metallothionein-3 can be accelerated by glutamate and by lowering the Zn-load of metallothionein-3 with EDTA. Glutamate facilitates the Cu(II) release, and Zn4-6-metallothionein-3 react more rapidly. These mechanisms are additive, proving the intricate and interconnected network of zinc and copper trafficking between biomols.
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39. 39
  Ngamchuea, K.; Batchelor-McAuley, C.; Compton, R. G. The Copper(II)-Catalyzed Oxidation of Glutathione. Chem. - Eur. J. 2016, 22 (44), 15937– 15944, DOI: 10.1002/chem.201603366
  39
  The Copper(II)-Catalyzed Oxidation of Glutathione
  Ngamchuea, Kamonwad; Batchelor-McAuley, Christopher; Compton, Richard G.
  Chemistry - A European Journal (2016), 22 (44), 15937-15944CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The kinetics and mechanisms of the copper(II)-catalyzed GSH (glutathione) oxidn. are examd. in the light of its biol. importance and in the use of blood and/or saliva samples for GSH monitoring. The rates of the free thiol consumption were measured spectrophotometrically by reaction with DTNB (5,5'-dithiobis-(2-nitrobenzoic acid)), showing that GSH is not auto-oxidized by oxygen in the absence of a catalyst. In the presence of Cu2+, reactions with two timescales were obsd. The first step (short timescale) involves the fast formation of a copper-glutathione complex by the cysteine thiol. The second step (longer timescale) is the overall oxidn. of GSH to GSSG (glutathione disulfide) catalyzed by copper(II). When the initial concns. of GSH are at least threefold in excess of Cu2+, the rate law is deduced to be -d[thiol]/dt=k[copper-glutathione complex][O2]0.5[H2O2]-0.5. The 0.5th reaction order with respect to O2 reveals a pre-equil. prior to the rate-detg. step of the GSSG formation. In contrast to [Cu2+] and [O2], the rate of the reactions decreases with increasing concns. of GSH. This inverse relationship is proposed to be a result of the competing formation of an inactive form of the copper-glutathione complex (binding to glutamic and/or glycine moieties).
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40. 40
  Gonzalez, P.; Vileno, B.; Bossak, K.; El Khoury, Y.; Hellwig, P.; Bal, W.; Hureau, C.; Faller, P. Cu(II) Binding to the Peptide Ala-His-His, a Chimera of the Canonical Cu(II)-Binding Motifs Xxx-His and Xxx-Zzz-His. Inorg. Chem. 2017, 56 (24), 14870, DOI: 10.1021/acs.inorgchem.7b01996
  40
  Cu(II) Binding to the Peptide Ala-His-His, a Chimera of the Canonical Cu(II)-Binding Motifs Xxx-His and Xxx-Zzz-His
  Gonzalez, Paulina; Vileno, Bertrand; Bossak, Karolina; El Khoury, Youssef; Hellwig, Petra; Bal, Wojciech; Hureau, Christelle; Faller, Peter
  Inorganic Chemistry (2017), 56 (24), 14870-14879CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
  Peptides and proteins with the N-terminal motifs NH2-Xxx-His and NH2-Xxx-Zzz-His form well established Cu(II)-complexes. The canonical peptides are Gly-His-Lys and Asp-Ala-His-Lys (from the wound healing factor and human serum albumin, resp.). Cu(II) is bound to NH2-Xxx-His via 3 nitrogens from the peptide and an external ligand in the equatorial plane (called 3N form here). In contrast, Cu(II) is bound to NH2-Xxx-Zzz-His via 4 nitrogens from the peptide in the equatorial plane (called 4N form here). These two motifs are not mutually exclusive, as the peptides with the sequence NH2-Xxx-His-His contain both of them. However, this chimera has never been really explored. In this work, we use a multispectroscopic approach to analyze the Cu(II)-binding to the chimeric peptide Ala-His-His (AHH). AHH is capable to form the 3N and 4N type complexes in a pH dependent manner. The 3N form predominates at pH ∼ 4-6.5 and the 4N form at ∼ pH 6.5-10. NMR expts. showed that at pH 8.5, where Cu(II) is almost exclusively bound in the 4N form, the Cu(II)-exchange between AHH or the amidated AHH-NH2 is fast, in comparison to the nonchimeric 4N form (AAH). Together the results show that the chimeric AHH can access both Cu(II) coordination types, that minor changes in the second (or further) coordination sphere can impact considerably the equil. between the forms and that Cu kinetic exchange is fast even when Cu-AHH is mainly in the 4N form.
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41. 41
  Gonzalez, P.; Bossak-Ahmad, K.; Vileno, B.; Wezynfeld, N. E.; El Khoury, Y.; Hellwig, P.; Hureau, C.; Bal, W.; Faller, P. Triggering Cu-Coordination Change in Cu(Ii)-Ala-His-His by External Ligands. Chem. Commun. 2019, 55 (56), 8110– 8113, DOI: 10.1039/C9CC03174J
  41
  Triggering Cu-coordination change in Cu(II)-Ala-His-His by external ligands
  Gonzalez, Paulina; Bossak-Ahmad, Karolina; Vileno, Bertrand; Wezynfeld, Nina E.; El Khoury, Youssef; Hellwig, Petra; Hureau, Christelle; Bal, Wojciech; Faller, Peter
  Chemical Communications (Cambridge, United Kingdom) (2019), 55 (56), 8110-8113CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
  Copper(II) forms well-known and stable complexes with peptides having histidine at position 2 (Xxx-His) or 3 (Xxx-Zzz-His). Their properties differ considerably due to the histidine positioning. Here we report that in the hybrid motif Xxx-His-His, the Cu(II)-complexes can be switched between the Xxx-His and the Xxx-Zzz-His coordination modes by addn. of external ligands.
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42. 42
  Hureau, C.; Eury, H.; Guillot, R.; Bijani, C.; Sayen, S.; Solari, P.-L.; Guillon, E.; Faller, P.; Dorlet, P. X-Ray and Solution Structures of CuIIGHK and CuIIDAHK Complexes: Influence on Their Redox Properties. Chem. - Eur. J. 2011, 17 (36), 10151– 10160, DOI: 10.1002/chem.201100751
  42
  X-Ray and Solution Structures of CuIIGHK and CuIIDAHK Complexes: Influence on Their Redox Properties
  Hureau, Christelle; Eury, Helene; Guillot, Regis; Bijani, Christian; Sayen, Stephanie; Solari, Pier-Lorenzo; Guillon, Emmanuel; Faller, Peter; Dorlet, Pierre
  Chemistry - A European Journal (2011), 17 (36), 10151-10160, S10151/1-S10151/17CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The Gly-His-Lys (GHK) peptide and the Asp-Ala-His-Lys (DAHK) sequences are naturally occurring high-affinity copper(II) chelators found in the blood plasma and are hence of biol. interest. A structural study of the copper complexes of these peptides was conducted in the solid state and in soln. by detg. their X-ray structures, and by using a large range of spectroscopies, including EPR and HYSCORE (hyperfine sub-level correlation), X-ray absorption and 1H and 13C NMR spectroscopy. The results indicate that the structures of [CuII(DAHK)] in the solid state and in soln. are similar and confirm the equatorial coordination sphere of NH2, two amidyl N and one imidazole N. Addnl., a water mol. is bound apically to CuII as revealed by the X-ray structure. As reported previously in the literature, [CuII(GHK)], which exhibits a dimeric structure in the solid state, forms a monomeric complex in soln. with three nitrogen ligands: NH2, amidyl and imidazole. The fourth equatorial site is occupied by a labile oxygen atom from a carboxylate ligand in the solid state. We probe that fourth position and study ternary complexes of [CuII(GHK)] with glycine or histidine. The CuII exchange reaction between different DAHK peptides is very slow, in contrast to [CuII(GHK)], in which the fast exchange was attributed to the presence of a [CuII(GHK)2] complex. The redox properties of [CuII(GHK)] and [CuII(DAHK)] were investigated by cyclic voltammetry and by measuring the ascorbate oxidn. in the presence of mol. oxygen. The measurements indicate that both CuII complexes are inert under moderate redox potentials. In contrast to [CuII(DAHK)], [CuII(GHK)] could be reduced to CuI around -0.62 V (vs. AgCl/Ag) with subsequent release of the Cu ion. These complete analyses of structure and redox activity of those complexes gave new insights with biol. impact and can serve as models for other more complicated CuII-peptide interactions.
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43. 43
  Atrián-Blasco, E.; Del Barrio, M.; Faller, P.; Hureau, C. Ascorbate Oxidation by Cu(Amyloid-â) Complexes: Determination of the Intrinsic Rate as a Function of Alterations in the Peptide Sequence Revealing Key Residues for Reactive Oxygen Species Production. Anal. Chem. 2018, 90 (9), 5909– 5915, DOI: 10.1021/acs.analchem.8b00740
  43
  Ascorbate Oxidation by Cu(Amyloid-β) Complexes: Determination of the Intrinsic Rate as a Function of Alterations in the Peptide Sequence Revealing Key Residues for Reactive Oxygen Species Production
  Atrian-Blasco, Elena; del Barrio, Melisa; Faller, Peter; Hureau, Christelle
  Analytical Chemistry (Washington, DC, United States) (2018), 90 (9), 5909-5915CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
  Along with aggregation of the amyloid-β (Aβ) peptide and subsequent deposit of amyloid plaques, oxidative stress is an important feature in Alzheimer's disease. Cu bound to Aβ is able to produce Reactive Oxygen Species (ROS) by the successive redns. of mol. dioxygen and the ROS such produced contribute to oxidative stress. In vitro, ROS prodn. parallels the ascorbate consumption, where ascorbate is the reductant that fuels the reactions. Because the affinity of Cu for Aβ is moderate compared to other biomols., the rate of ascorbate consumption is a combination of two contributions. The first one is due to peptide-unbound Cu and the second one to peptide-bound Cu complexes. In the present article, we aim at detg. the amts. of the second contribution in the global ascorbate consumption process. It is defined as the intrinsic rate of ascorbate oxidn., which math. corresponds to the rate at an infinite peptide to Cu ratio, i.e. without any contribution from peptide-unbound Cu. We show that for the wild-type Cu(Aβ) complex, this value equals 10% of the value obtained for peptide-unbound Cu and that this value is strongly dependent on peptide alterations. By examn. of the dependence of the intrinsic rate of ascorbate oxidn., followed by UV-Vis spectroscopy, for several altered peptides, we det. some of the key residues that influence ROS prodn.
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44. 44
  Atrián-Blasco, E.; Gonzalez, P.; Santoro, A.; Alies, B.; Faller, P.; Hureau, C. Cu and Zn Coordination to Amyloid Peptides: From Fascinating Chemistry to Debated Pathological Relevance. Coord. Chem. Rev. 2018, 371, 38– 55, DOI: 10.1016/j.ccr.2018.04.007
  44
  Cu and Zn coordination to amyloid peptides: From fascinating chemistry to debated pathological relevance
  Atrian-Blasco, Elena; Gonzalez, Paulina; Santoro, Alice; Alies, Bruno; Faller, Peter; Hureau, Christelle
  Coordination Chemistry Reviews (2018), 371 (), 38-55CODEN: CCHRAM; ISSN:0010-8545. (Elsevier B.V.)
  A review. Several diseases share misfolding of different peptides and proteins as a key feature for their development. This is the case of important neurodegenerative diseases such as Alzheimer's and Parkinson's diseases and type II diabetes mellitus. Furthermore, metal ions such as copper and zinc might play an important role upon interaction with amyloidogenic peptides and proteins, which could impact their aggregation and toxicity abilities. In this review, the different coordination modes proposed for copper and zinc with amyloid-β, α-synuclein and IAPP will be reviewed as well as their impact on the aggregation, and ROS prodn. in the case of copper. In addn., a special focus will be given to the mutations that affect metal binding and lead to familial cases of the diseases. Different modifications of the peptides that have been obsd. in vivo and could be relevant for the coordination of metal ions are also described.
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Copper Transporters? Glutathione Reactivity of Products of Cu–Aβ Digestion by Neprilysin
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Copper Transporters? Glutathione Reactivity of Products of Cu–Aβ Digestion by Neprilysin
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