4,4'-dimethoxychalcone exerts neuroprotective effects in Alzheimer's disease mice by activating the Keap1/Nrf2 signaling pathway.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with no effective therapies. 4,4'-Dimethoxychalcone (DMC) is a natural chalcone extracted from Angelica keiskei (Miq.) Koidz and Angelica sinensis (Oliv.) Diels, which could promote autophagy and prolong lifespan. However, the neuroprotective effects and mechanisms of DMC on AD mice have not been reported. In this study, we proved that DMC treatment significantly mitigated cognitive impairment and depressive behavior, ameliorated blood-brain barrier permeability and amyloid β pathology, and inhibited p-Tau expression in 5 × FAD mice. Also, DMC suppressed glial cell activation, enhanced neurogenesis, and decreased oxidative stress in vivo and in vitro by activating the Kelch-like ECH-associated protein1 (Keap1)/nuclear factor-erythrocyte 2-associated factor 2 (Nrf2) signaling pathway. However, Brusatol, an inhibitor of the Keap1/Nrf2 signalling, partly attenuated the neuroprotective effects of DMC on lipopolysaccharide-induced HT22 cells injury and 5 × FAD mice. In conclusion, DMC exhibited neuroprotective effects on 5 × FAD mice via the activation of Keap1/Nrf2 signalling pathway. Thus, DMC may be a promising therapeutic drug for AD.