Journal
CURRENT ALZHEIMER RESEARCH
Volume 11, Issue 2, Pages 128-136Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1567205011666140130150108
Keywords
ABAD inhibitors; adenosine-5 '-triphosphate; amyloid beta; benzothiazole amino phosphonates; cytochrome c oxidase; mitochondrial dysfunction
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Funding
- National Institute on Aging, National Institute of Neurological Disorder and Stroke [R37AG037319, RO1NS65482]
- University of Kansas Alzheimer's Disease Center [P30 AG035982]
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Amyloid beta (A beta) binding alcohol dehydrogenase (ABAD) is a cellular cofactor for promoting (A beta)-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 A beta-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.
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