Dietary (-)-epicatechin as a potent inhibitor of βγ-secretase amyloid precursor protein processing

Flavonoids, a group of dietary polyphenols have been shown to possess cognitive health benefits. Epidemiologic evidence suggests that they could play a role in risk reduction in dementia. Amyloid precursor protein processing and the subsequent generation of amyloid beta (A beta) are central to the pathogenesis of Alzheimer's disease, as soluble, oligomeric A beta is thought to be the toxic species driving disease progression. We undertook an in vitro screen to identify flavonoids with bioactivity at beta gamma-mediated amyloid precursor protein processing, which lead to identification of a number of flavonoids bioactive at 100 nM. Because of known bioavailability, we investigated the catechin family further and identified epigallocatechin and (-)-epicatechin as potent (nanomolar) inhibitors of amyloidogenic processing. Supporting this finding, we have shown reduced A beta pathology and A beta levels following short term, a 21-day oral delivery of (-)-epicatechin in 7-month-old TASTPM mice. Further, in vitro mechanistic studies suggest this is likely because of indirect BACE1 inhibition. Taken together, our results suggest that orally delivered (-)-epicatechin may be a potential prophylactic for Alzheimer's disease. (C) 2015 The Authors. Published by Elsevier Inc. All rights reserved.