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Distinct Aggregation Behavior of N-Terminally Truncated Aβ4–42 Over Aβ1–42 in the Presence of Zn(II)

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Download Hi-Res ImageDownload to MS-PowerPointCite This:ACS Chem. Neurosci. 2025, 16, 4, 732-744
    Research Article

    Distinct Aggregation Behavior of N-Terminally Truncated Aβ4–42 Over Aβ1–42 in the Presence of Zn(II)
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    • Chanju Na
      Chanju Na
      Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
      More by Chanju Na
    • Mingeun Kim
      Mingeun Kim
      Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
      More by Mingeun Kim
    • Gunhee Kim
      Gunhee Kim
      Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
      More by Gunhee Kim
    • Yuxi Lin
      Yuxi Lin
      Biopharmaceutical Research Center, Korea Basic Science Institute (KBSI), Ochang, Chungbuk 28119, Republic of Korea
      More by Yuxi Lin
      Orcidhttps://orcid.org/0000-0002-5936-0954
    • Young-Ho Lee
      Young-Ho Lee
      Biopharmaceutical Research Center, Korea Basic Science Institute (KBSI), Ochang, Chungbuk 28119, Republic of Korea
      Bio-Analytical Science, University of Science and Technology (UST), Daejeon 34113, Republic of Korea
      Graduate School of Analytical Science and Technology (GRAST), Chungnam National University, Daejeon 34134, Republic of Korea
      Department of Systems Biotechnology, Chung-Ang University (CAU), Gyeonggi 17546, Republic of Korea
      Frontier Research Institute for Interdisciplinary Sciences (FRIS), Tohoku University, Sendai, Miyagi 980-8578, Japan
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      Orcidhttps://orcid.org/0000-0002-8441-5814
    • Wojciech Bal*
      Wojciech Bal
      Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawińskiego 5a, Warsaw 02-106, Poland
      *Email: [email protected]
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      Orcidhttps://orcid.org/0000-0003-3780-083X
    • Eunju Nam*
      Eunju Nam
      Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
      Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts 02115, United States
      Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States
      *Email: [email protected]
      More by Eunju Nam
      Orcidhttps://orcid.org/0000-0003-0801-9331
    • Mi Hee Lim*
      Mi Hee Lim
      Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
      *Email: [email protected]
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      Orcidhttps://orcid.org/0000-0003-3377-4996
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    ACS Chemical Neuroscience

    Cite this: ACS Chem. Neurosci. 2025, 16, 4, 732–744
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    https://doi.org/10.1021/acschemneuro.4c00831
    Published January 30, 2025
    Copyright © 2025 American Chemical Society
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    Abstract

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    The deposition of amyloid-β (Aβ) aggregates and metal ions within senile plaques is a hallmark of Alzheimer’s disease (AD). Among the modifications observed in Aβ peptides, N-terminal truncation at Phe4, yielding Aβ4–x, is highly prevalent in AD-affected brains and significantly alters Aβ’s metal-binding and aggregation profiles. Despite the abundance of Zn(II) in senile plaques, its impact on the aggregation and toxicity of Aβ4–x remains unexplored. Here, we report the distinct aggregation behavior of N-terminally truncated Aβ, specifically Aβ4–42, in the absence and presence of either Zn(II), Aβ seeds, or both, and compare it to that of full-length Aβ1–42. Our findings reveal notable differences in the aggregation profiles of Aβ4–42 and Aβ1–42, largely influenced by their different Zn(II)-binding properties. These results provide insights into the mechanisms underlying the distinct aggregation behavior of truncated and full-length Aβ in the presence of Zn(II), contributing to a deeper understanding of AD pathology.

    Copyright © 2025 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acschemneuro.4c00831.

    • Purity of Aβ peptides; electronic absorption spectra of Aβ peptides; schematic experimental procedures; aggregation kinetics of Aβ peptides in the absence and presence of Zn(II) with and without Aβ4–42 seeds; turbidity of Aβ aggregates with and without Zn(II); TEM images of the resultant Aβ assemblies produced with and without either Zn(II), Aβ1–42 seeds, or both; cell viability of Aβ with and without either Zn(II), Aβ1–42 seeds, or both; aggregation kinetics and secondary structures of Aβ fragments and their mutants with and without Zn(II); ITC binding isotherms obtained from the titration of Zn(II) into Aβ4–16 with various fitting models; Zn(II)-binding studies of Aβ1–16 mutants (Figures S1–S12) (PDF)

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    ACS Chemical Neuroscience

    Cite this: ACS Chem. Neurosci. 2025, 16, 4, 732–744
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acschemneuro.4c00831
    Published January 30, 2025
    Copyright © 2025 American Chemical Society
    Request reuse permissions

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