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    Mutations in the Amyloid-β Protein Precursor Reduce Mitochondrial Function and Alter Gene Expression Independent of 42-Residue Amyloid-β Peptide

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    Pope_2022.pdf (1.237Mb)
    Issue Date
    2021-09-28
    Author
    Pope, Chad A.
    Wilkins, Heather M.
    Swerdlow, Russell H.
    Wolfe, Michael S.
    Publisher
    IOS Press
    Type
    Article
    Article Version
    Scholarly/refereed, author accepted manuscript
    Rights
    Copyright The Authors (2021).
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    Abstract
    Background:Dominant missense mutations in the amyloid-β protein precursor (AβPP) cause early-onset familial Alzheimer’s disease (FAD) and are associated with changes in the production or properties of the amyloid-β peptide (Aβ), particularly of the 42-residue variant (Aβ42) that deposits in the Alzheimer’s disease (AD) brain. Recent findings, however, show that FAD mutations in AβPP also lead to increased production of longer Aβ variants of 45–49 residues in length. Objective:We aimed to test neurotoxicity of Aβ42 vis-á-vis longer variants, focusing specifically on mitochondrial function, as dysfunctional mitochondria are implicated in the pathogenesis of AD. Methods:We generated SH-SY5Y human neuroblastoma cells stably expressing AβPP mutations that lead to increased production of long Aβ peptides with or without Aβ42. These AβPP-expressing cells were tested for oxygen consumption rates (OCR) under different conditions designed to interrogate mitochondrial function. These cell lines were also examined for expression of genes important for mitochondrial or neuronal structure and function. Results:The mutant AβPP-expressing cells showed decreased basal OCRs as well as decreased OCRs associated with mitochondrial ATP production, even more so in the absence of Aβ42 production. Moreover, mutant AβPP-expressing cells producing longer forms of Aβ displayed altered expression of certain mitochondrial- and neuronal-associated genes, whether or not Aβ42 was produced. Conclusion:These findings suggest that mutant AβPP can cause mitochondrial dysfunction that is associated with long Aβ but not with Aβ42.
    URI
    http://hdl.handle.net/1808/32753
    DOI
    https://doi.org/10.3233/JAD-210366
    Collections
    • Medicinal Chemistry Scholarly Works [244]
    Citation
    Pope, C. A., Wilkins, H. M., Swerdlow, R. H., & Wolfe, M. S. (2021). Mutations in the Amyloid-β Protein Precursor Reduce Mitochondrial Function and Alter Gene Expression Independent of 42-Residue Amyloid-β Peptide. Journal of Alzheimer's disease : JAD, 83(3), 1039–1049. https://doi.org/10.3233/JAD-210366

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    KU Libraries
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    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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