Aging is accompanied by deficits in cognitive function and neuronal degeneration or loss. Quercetin is a flavonoid that exhibits powerful antioxidant activity. This study evaluated the protective effects and mechanisms of quercetin in D-galactose-induced neurotoxicity in mice. Quercetin was administered daily at doses of 20 or 50 mg/kg in D-galactose-injected (50mg/kg/subcutaneous (s.c.)) mice for eight weeks. Morris water maze tests demonstrated that quercetin significantly improved learning and memory compared to o D-galactose-treated control mice. Quercetin also prevented changes in the neuronal cell morphology and apoptosis in the hippocampus as well as increased the expression of Nrf2, HO-1 and SOD in o -galactose-treated mice. Treatment with the Nrf2 inhibitor Brusatol reversed the effects of quercetin on HO-1 and SOD expression as well as neuronal cell protection. In conclusion, quercetin protected mice from o -galactose-induced cognitive functional impairment and neuronal cell apoptosis via activation of the Nrf2-ARE signaling pathway. (C) 2017 Elsevier Inc. All rights reserved.