Tannic acid is a natural β-secretase inhibitor that prevents cognitive impairment and mitigates Alzheimer-like pathology in transgenic mice.
Amyloid precursor protein (APP) proteolysis is essential for production of amyloid-β (Aβ) peptides that form β-amyloid plaques in brains of Alzheimer disease (AD) patients. Recent focus has been directed toward a group of naturally occurring anti-amyloidogenic polyphenols known as flavonoids. We orally administered the flavonoid tannic acid (TA) to the transgenic PSAPP mouse model of cerebral amyloidosis (bearing mutant human APP and presenilin-1 transgenes) and evaluated cognitive function and AD-like pathology. Consumption of TA for 6 months prevented transgene-associated behavioral impairment including hyperactivity, decreased object recognition, and defective spatial reference memory, but did not alter nontransgenic mouse behavior. Accordingly, brain parenchymal and cerebral vascular β-amyloid deposits and abundance of various Aβ species including oligomers were mitigated in TA-treated PSAPP mice. These effects occurred with decreased cleavage of the β-carboxyl-terminal APP fragment, lowered soluble APP-β production, reduced β-site APP cleaving enzyme 1 protein stability and activity, and attenuated neuroinflammation. As in vitro validation, we treated well characterized mutant human APP-overexpressing murine neuron-like cells with TA and found significantly reduced Aβ production associated with less amyloidogenic APP proteolysis. Taken together, these results raise the possibility that dietary supplementation with TA may be prophylactic for AD by inhibiting β-secretase activity and neuroinflammation and thereby mitigating AD pathology.
Department of Biomedical Sciences, Saitama Medical Center and University, Kawagoe, Saitama 350-8550, Japan. t_mori@saitama-med.ac.jp
Takashi
T
Mori
Kavon
K
Rezai-Zadeh
Naoki
N
Koyama
Gary W
GW
Arendash
Haruyasu
H
Yamaguchi
Nobuto
N
Kakuda
Yuko
Y
Horikoshi-Sakuraba
Jun
J
Tan
Terrence
T
Town
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002460:Cell Line; D016657:Cerebral Amyloid Angiopathy / Q000188:drug therapy / Q000473:pathology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy / Q000473:pathology; D005260:Female; D005911:Gliosis / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D013634:Tannins / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D013634:Tannins; C078592:amyloid beta-protein (1-40); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse