Potent anti-amyloidogenic and fibril-destabilizing effects of polyphenols in vitro: implications for the prevention and therapeutics of Alzheimer's disease.
Cerebral deposition of amyloid beta-peptide (Abeta) in the brain is an invariant feature of Alzheimer's disease (AD). A consistent protective effect of wine consumption on AD has been documented by epidemiological studies. In the present study, we used fluorescence spectroscopy with thioflavin T and electron microscopy to examine the effects of wine-related polyphenols (myricetin, morin, quercetin, kaempferol (+)-catechin and (-)-epicatechin) on the formation, extension, and destabilization of beta-amyloid fibrils (fAbeta) at pH 7.5 at 37 degrees C in vitro. All examined polyphenols dose-dependently inhibited formation of fAbeta from fresh Abeta(1-40) and Abeta(1-42), as well as their extension. Moreover, these polyphenols dose-dependently destabilized preformed fAbetas. The overall activity of the molecules examined was in the order of: myricetin = morin = quercetin > kaempferol > (+)-catechin = (-)-epicatechin. The effective concentrations (EC50) of myricetin, morin and quercetin for the formation, extension and destabilization of fAbetas were in the order of 0.1-1 micro m. In cell culture experiments, myricetin-treated fAbeta were suggested to be less toxic than intact fAbeta, as demonstrated by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. Although the mechanisms by which these polyphenols inhibit fAbeta formation from Abeta, and destabilize pre-formed fAbetain vitro are still unclear, polyphenols could be a key molecule for the development of preventives and therapeutics for AD.
Ono
Kenjiro
K
Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8640, Japan.
Yoshiike
Yuji
Y
Takashima
Akihiko
A
Hasegawa
Kazuhiro
K
Naiki
Hironobu
H
Yamada
Masahito
M
D000544:Alzheimer Disease / Q000188:drug therapy / Q000517:prevention & control; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000187:drug effects; D052160:Benzothiazoles; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008854:Microscopy, Electron; D010446:Peptide Fragments / Q000737:chemistry; D010636:Phenols / Q000737:chemistry* / Q000494:pharmacology*; D011108:Polymers / Q000737:chemistry* / Q000494:pharmacology*; D011794:Quercetin / Q000737:chemistry / Q000494:pharmacology; D013050:Spectrometry, Fluorescence; D013778:Tetrazolium Salts; D013844:Thiazoles / Q000737:chemistry; D047309:Flavones
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D005419:Flavonoids; D010446:Peptide Fragments; D010636:Phenols; D011108:Polymers; D011794:Quercetin; D013778:Tetrazolium Salts; D013844:Thiazoles; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C009462:thioflavin T; C040015:myricetin; C008548:morin; D047309:Flavones; C022616:thiazolyl blue