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-beta (A beta) peptides that form beta-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. Weorally 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 beta-amyloid deposits and abundance of various A beta species including oligomers were mitigated in TA-treated PSAPP mice. These effects occurred with decreased cleavage of the beta-carboxyl-terminal APP fragment, lowered soluble APP-beta production, reduced beta-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 A beta 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 beta-secretase activity and neuroinflammation and thereby mitigating AD pathology.