Unexpected beta-amyloid production by middle doses of resveratrol through stabilization of APP protein and AMPK-mediated inhibition of trypsin-like proteasome activity in a cell model of Alzheimer's disease

Resveratrol is a drug candidate used for Alzheimer's disease (AD) and shows beneficial effects in various toxicity and production models, although recent clinical trial data did not show satisfactory results. Here we demonstrated the potential side effects of resveratrol in AD. We demonstrated resveratrol concentration- and time-dependent Aβ production using Aβ secreted cellular model and analyzed resveratrol-related molecular signaling. In Swedish mutant of APP (APPsw) stably expressing cells, treatment with a middle dose of resveratrol for 24 h unexpectedly increased Aβ production, but higher concentrations or shorter treatment durations did not. Resveratrol-mediated Aβ production was caused by an increase in APP protein levels associated with proteasome-dependent regulation of APP stability. Inhibition of AMPK, cAMP production, and epac1 attenuated Aβ production and APP increase by resveratrol, which blocked the inhibition of trypsin-like proteasomal activity. In addition, high-dose resveratrol decreased Aβ secretion and β-secretase activity at any treatment duration. Our data suggest that an appropriate dose of resveratrol can paradoxically increase Aβ production via stabilization of APP protein in an AMPK-proteasome signaling-dependent manner, which provides mechanistic insights into prior unsatisfactory clinical outcomes and the future clinical use of resveratrol. [Display omitted] •Middle-dose resveratrol increases Aβproduction after 24 h, but not with shorter treatment durations.•High-dose resveratrol reduced Aβ levels and β-secretase activity but was toxic.•Resveratrol-mediated Aβ production is caused by proteasomal stabilization of APP protein.•The increase of Aβ is closely associated with substrate-specific AMPK activity.•The cAMP-epac1-AMPK pathway is a major mechanism for the resveratrol-mediated reduction of trypsin-like proteasome activity.