Identification of human ABAD inhibitors for rescuing Aβ-mediated 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.

journal_name

Curr Alzheimer Res

authors

Valaasani KR,Sun Q,Hu G,Li J,Du F,Guo Y,Carlson EA,Gan X,Yan SS

doi

10.2174/1567205011666140130150108

subject

Has Abstract

pub_date

2014-02-01 00:00:00

pages

128-36

issue

2

eissn

1567-2050

issn

1875-5828

pii

CAR-EPUB-58904

journal_volume

11

pub_type

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