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    Inhibition of Amyloid-β (Aβ) Peptide-Binding Alcohol Dehydrogenase-Aβ Interaction Reduces Aβ Accumulation and Improves Mitochondrial Function in a Mouse Model of Alzheimer's Disease

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    Issue Date
    2011-02-09
    Author
    Yao, Jun
    Du, Heng
    Yan, Shiqiang
    Fang, Fang
    Wang, Chaodong
    Lue, Lih-Fen
    Guo, Lan
    Chen, Doris
    Stern, David M.
    Moore, Frank J. Gunn
    Chen, John Xi
    Arancio, Ottavio
    Yan, Shirley ShiDu
    Publisher
    Society for Neuroscience
    Type
    Article
    Article Version
    Scholarly/refereed, publisher version
    Metadata
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    Abstract
    Amyloid-β (Aβ) peptide-binding alcohol dehydrogenase (ABAD), an enzyme present in neuronal mitochondria, exacerbates Aβ-induced cell stress. The interaction of ABAD with Aβ exacerbates Aβ-induced mitochondrial and neuronal dysfunction. Here, we show that inhibition of the ABAD-Aβ interaction, using a decoy peptide (DP) in vitro and in vivo, protects against aberrant mitochondrial and neuronal function and improves spatial learning/memory. Intraperitoneal administration of ABAD-DP [fused to the transduction of human immunodeficiency virus 1-transactivator (Tat) protein and linked to the mitochondrial targeting sequence (Mito) (TAT-mito-DP) to transgenic APP mice (Tg mAPP)] blocked formation of ABAD-Aβ complex in mitochondria, increased oxygen consumption and enzyme activity associated with the mitochondrial respiratory chain, attenuated mitochondrial oxidative stress, and improved spatial memory. Similar protective effects were observed in Tg mAPP mice overexpressing neuronal ABAD decoy peptide (Tg mAPP/mito-ABAD). Notably, inhibition of the ABAD-Aβ interaction significantly reduced mitochondrial Aβ accumulation. In parallel, the activity of mitochondrial Aβ-degrading enzyme PreP (presequence peptidase) was enhanced in Tg mAPP mitochondria expressing the ABAD decoy peptide. These data indicate that segregating ABAD from Aβ protects mitochondria/neurons from Aβ toxicity; thus, ABAD-Aβ interaction is an important mechanism underlying Aβ-mediated mitochondrial and neuronal perturbation. Inhibitors of ABAD-Aβ interaction may hold promise as targets for the prevention and treatment of Alzheimer's disease.
    Description
    This is the publisher's version, also available electronically from http://www.jneurosci.org/content/31/6/2313
    URI
    http://hdl.handle.net/1808/14810
    DOI
    https://doi.org/10.1523/JNEUROSCI.4717-10.2011
    ISSN
    0270-6474
    Collections
    • Pharmacy Scholarly Works [286]
    Citation
    Yao, Jun (2011). Inhibition of Amyloid-β (Aβ) Peptide-Binding Alcohol Dehydrogenase-Aβ Interaction Reduces Aβ Accumulation and Improves Mitochondrial Function in a Mouse Model of Alzheimer's Disease. Journal of Neuroscience 31(6):2313-20. http://www.dx.doi.org/10.1523/JNEUROSCI.4717-10.2011

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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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