Identification of Human ABAD Inhibitors for Rescuing Aβ-Mediated Mitochondrial Dysfunction
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Issue Date
2014-07-06Author
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
Metadata
Show full item recordAbstract
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.
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- Pharmacy Scholarly Works [293]
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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