In this study, we identified that antidepressant agomelatine improved cognitive deficits and ameliorated AD-like pathologies, including Aβ deposition, tau protein hyperphosphorylation, and neuroinflammation in APP/PS1 mice, via activating DHCR24 signaling and inhibiting Akt/mTOR and Hes1/Notch1 signaling pathway. Here, HES1 is linked to Alzheimer disease.