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

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

Volume: 11 Issue: 2

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

Affiliation:

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

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.

Cite this article as:

Valaasani R. Koteswara, Sun Qinru, Hu Gang, Li Jianping, Du Fang, Guo Yaopeng, Carlson A. Emily, Gan Xueqi and Yan S. Shirley, Identification of Human ABAD Inhibitors for Rescuing Aβ-Mediated Mitochondrial Dysfunction, Current Alzheimer Research 2014; 11 (2) . https://dx.doi.org/10.2174/1567205011666140130150108