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

NEUROBIOLOGY OF AGING

卷:36

Article

Cox, Carla J.¹  Choudhry, Fahd²  Peacey, Eleanor²  Perkinton, Michael S.²  Richardson, Jill C.³  Howlett, David R.²  Lichtenthaler, Stefan F.^4,5,6  Francis, Paul T.²  Williams, Robert J.¹ 

[1] Univ Bath, Dept Biol & Biochem, Bath BA2 7AY, Avon, England

[2] Kings Coll London, Wolfson Ctr Age Related Dis, London WC2R 2LS, England

[3] GlaxoSmithKline, Med Res Ctr, Neurosci Therapy Area Unit, Brentford, Herts, England

[4] Tech Univ Munich, Klinikum Rechts Isar, D-80290 Munich, Germany

[5] German Ctr Neurodegenerat Dis DZNE, Munich, Germany

[6] Munich Cluster Syst Neurol SyNergy, Munich, Germany

关键词: Flavanol;    Flavonoid;    Alzheimer's disease;    TASTPM;    BACE1;    Amyloid pathology;    A beta;    Dietary polyphenolic;    Dementia;    APP processing;    Catechin;   

DOI  :  10.1016/j.neurobiolaging.2014.07.032

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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