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    Identification of Human ABAD Inhibitors for Rescuing Aβ-Mediated Mitochondrial Dysfunction

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    Issue Date
    2014-07-06
    Author
    Valasani, Koteswara Rao
    Sun, Qinru
    Hu, Gang
    Li, Jianping
    Du, Fang
    Guo, Yaopeng
    Carlson, Emily A.
    Gan, Xueqi
    Yan, Shirley ShiDu
    Publisher
    Bentham Science Publishers
    Type
    Article
    Article Version
    Scholarly/refereed, author accepted manuscript
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    Abstract
    Amyloid beta (Aβ) binding alcohol dehydrogenase (ABAD) is a cellular cofactor for promoting (Aβ)-mediated mitochondrial and neuronal dysfunction, and cognitive decline in transgenic Alzheimer's disease (AD) mouse models. Targeting mitochondrial ABAD may represent a novel therapeutic strategy against AD. Here, we report the biological activity of small molecule ABAD inhibitors. Using in vitro surface plasmon resonance (SPR) studies, we synthesized compounds with strong binding affinities for ABAD. Further, these ABAD inhibitors (ABAD-4a and 4b) reduced ABAD enzyme activity and administration of phosphonate derivatives of ABAD inhibitors antagonized calcium-mediated mitochondrial swelling. Importantly, these compounds also abolished Aβ-induced mitochondrial dysfunction as shown by increased cytochrome c oxidase and adenosine-5′-triphosphate levels, suggesting protective mitochondrial function effects of these synthesized compounds. Thus, these compounds are potential candidates for further pharmacologic development to target ABAD to improve mitochondrial function.
    URI
    http://hdl.handle.net/1808/23278
    DOI
    https://doi.org/10.2174/1567205011666140130150108
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    • Pharmacy Scholarly Works [280]
    Citation
    Valaasani, Koteswara, Qinru Sun, Gang Hu, Jianping Li, Fang Du, Yaopeng Guo, Emily Carlson, Xueqi Gan, and Shirley Yan. "Identification of Human ABAD Inhibitors for Rescuing Aβ-Mediated Mitochondrial Dysfunction." Current Alzheimer Research 11.2 (2014): 128-36.

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    KU Libraries
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    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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