Identification of human ABAD inhibitors for rescuing Aβ-mediated mitochondrial dysfunction.
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.
Koteswara R
KR
Valaasani
Qinru
Q
Sun
Gang
G
Hu
Jianping
J
Li
Fang
F
Du
Yaopeng
Y
Guo
Emily A
EA
Carlson
Xueqi
X
Gan
2099 Constant Avenue, University of Kansas, Lawrence, KS 66047, USA. shidu@ku.edu.
Shirley S
SS
Yan
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology*; D010446:Peptide Fragments / Q000633:toxicity*; D011994:Recombinant Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D011994:Recombinant Proteins; C075222:amyloid beta-protein (1-42); D015094:3-Hydroxyacyl CoA Dehydrogenases; C108634:HSD17B10 protein, human