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

Author(s): Koteswara R. Valaasani, Qinru Sun, Gang Hu, Jianping Li, Fang Du, Yaopeng Guo, Emily A. Carlson, Xueqi Gan, Shirley S. Yan.

Journal Name: Current Alzheimer Research

Volume 11 , Issue 2 , 2014

Become EABM
Become Reviewer

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 activity 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.

Keywords: ABAD inhibitors, adenosine-5'-triphosphate, amyloid beta, benzothiazole amino phosphonates, cytochrome c oxidase, mitochondrial dysfunction.

Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 11
ISSUE: 2
Year: 2014
Page: [128 - 136]
Pages: 9
DOI: 10.2174/1567205011666140130150108
Price: $58

Article Metrics

PDF: 31