title: Dietary (-)-epicatechin as a potent inhibitor of βγ-secretase amyloid precursor protein processing.
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.
authors.affiliation: Department of Biology and Biochemistry, University of Bath, UK.
authors.forename: Carla J
authors.initials: CJ
authors.lastname: Cox
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College London, London, UK.
authors.forename: Fahd
authors.initials: F
authors.lastname: Choudhry
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College London, London, UK.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Peacey
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College London, London, UK.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Perkinton
authors.affiliation: Neurosciences Therapy Area Unit, GlaxoSmithKline, Medicines Research Centre, Hertfordshire, UK.
authors.forename: Jill C
authors.initials: JC
authors.lastname: Richardson
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College London, London, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: Howlett
authors.affiliation: Neuroproteomics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Stefan F
authors.initials: SF
authors.lastname: Lichtenthaler
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College London, London, UK.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Francis
authors.affiliation: Department of Biology and Biochemistry, University of Bath, UK. Electronic address: r.j.williams@bath.ac.uk.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Williams
mesh_terms: D000284:Administration, Oral; D000544:Alzheimer Disease / Q000235:genetics* / Q000517:prevention & control*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002392:Catechin / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000494:pharmacology*; D002478:Cells, Cultured; D018450:Disease Progression; D008297:Male; D008822:Mice, Transgenic
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002392:Catechin; C057580:gallocatechol
keywords: APP processing; Alzheimer's disease; Amyloid pathology; Aβ; BACE1; Catechin; Dementia; Dietary polyphenolic; Flavanol; Flavonoid; TASTPM