Diosmin reduces cerebral Aβ levels, tau hyperphosphorylation, neuroinflammation, and cognitive impairment in the 3xTg-AD mice

•Diosmin reduced AD pathology and cognitive impairment in the 3xTg-AD mouse model through GSK-3 and TRPC6-related mechanisms.•Diosmetin inhibited GSK-3β, APP γ-secretase, Aβ generation, tau hyperphosphorylation and microglial activation in vitro.•Both diosmin and its major metabolite diosmetin could be considered as potential candidates for novel anti-AD therapy.

Naturally-occurring bioactive flavonoids such as diosmin significantly reduces amyloid beta (Aβ) associated pathology in Alzheimer's disease (AD) mouse models. In the present study, oral administration of diosmin reduced cerebral Aβ oligomer levels, tau-hyperphosphorylation and cognitive impairment in the 3xTg-AD mouse model through glycogen synthase kinase-3 (GSK-3) and transient receptor potential canonical 6-related mechanisms. Diosmetin, one major bioactive metabolite of diosmin, increased inhibitory GSK-3β phosphorylation, while selectively reducing γ-secretase activity, Aβ generation, tau hyperphosphorylation and pro-inflammatory activation of microglia in vitro, without altering Notch processing. Therefore, both diosmin and diosmetin could be considered as potential candidates for novel anti-AD therapy.

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