Quercetin inhibits cytotoxicity of PC12 cells induced by amyloid-beta 25-35 via stimulating estrogen receptor alpha, activating ERK1/2, and inhibiting apoptosis

The accumulation of beta-amyloid (A beta) in the brain plays an important role in the pathogenesis of Alzheimer's disease (AD). The lack of estrogen is one of the risk factors for AD. Quercetin is a phytoestrogen with a chemical structure similar to that of estrogen. However, the mechanism by which quercetin prevents AD is unclear. PC12 cells were cultured with A beta(25-35) for 24 h. Then the cells were further treated with 17 beta-estradiol, genistein, and quercetin for another 24 h, respectively. Next, ICI182780 and U0126 were used to study the mechanisms of estrogen-like neuroprotection. Methyl thiazolyl tetrazolium (MTT) assay was performed to detect cell survival. The protein expression was analyzed by immunofluorescence and western blot. The survival of PC12 cells induced by A beta(25-35) was increased by quercetin. The levels of estrogen receptor alpha (ER alpha) and p-extracellular signal-regulated kinase (ERK)1/2 were improved by quercetin, but not those of ER beta. On the contrary, Bcl-2/Bax was increased and the expression of Caspase-3 was decreased. When the cell was pretreated with ICI182780, the p-ERK1/2 and Bcl-2/Bax ratio was decreased, but Caspase-3 expression was increased. In addition, pretreatment with U0126 would reduce Bcl-2/Bax ratio and increase Caspase-3 protein expression. Conclusively, quercetin plays a neuroprotective role through the ER pathway and the mitogen-activated protein kinase (MAPK) pathway. The MAPK signaling pathways could also be activated by quercetin via the mediation of ER alpha.