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

Carla J Cox, Fahd Choudhry, Eleanor Peacey, Michael S Perkinton, Jill C Richardson, David R Howlett, Stefan F Lichtenthaler, Paul T Francis, Robert J Williams

Research output: Contribution to journalArticlepeer-review

51 Citations (Scopus)
93 Downloads (Pure)

Abstract

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 (Aβ) are central to the pathogenesis of Alzheimer's disease, as soluble, oligomeric Aβ is thought to be the toxic species driving disease progression. We undertook an in vitro screen to identify flavonoids with bioactivity at βγ-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 Aβ pathology and Aβ 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.
Original languageEnglish
Pages (from-to)178-187
Number of pages10
JournalNeurobiology of Aging
Volume36
Issue number1
Early online date30 Jul 2014
DOIs
Publication statusPublished - 1 Jan 2015

Keywords

  • Flavanol
  • Flavonoid
  • Alzheimer Disease
  • TASTPM
  • BACE1
  • Amyloid pathology
  • Dietary polyphenolic
  • Dementia
  • APP processing
  • Catechin

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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