Attenuation of estrogen and its receptors in the post-menopausal stage exacerbates dyslipidemia and leads to cognitive impairment.

Cognitive dysfunction increases as menopause progresses. We previously found that estrogen receptors (ERs) contribute to dyslipidemia, but the specific relationship between ERs, dyslipidemia and cognitive dysfunction remains poorly understood. In the present study, we analyzed sequencing data from female hippocampus and normal breast aspirate samples from normal and Alzheimer's disease (AD) women, and the results suggest that abnormal ERs signaling is associated with dyslipidemia and cognitive dysfunction. We replicated a mouse model of dyslipidemia and postmenopausal status in LDLR^-/- mice and treated them with β-estradiol or simvastatin, and found that ovariectomy in LDLR^-/- mice led to an exacerbation of dyslipidemia and increased hippocampal apoptosis and cognitive impairment, which were associated with reduced estradiol levels and ERα, ERβ and GPER expression. In vitro, a lipid overload model of SH-SY-5Y cells was established and treated with inhibitors of ERs. β-estradiol or simvastatin effectively attenuated dyslipidemia-induced neuronal apoptosis via upregulation of ERs, whereas ERα, ERβ and GPER inhibitors together abolished the protective effect of simvastatin on lipid-induced neuronal apoptosis. We conclude that decreased estrogen and its receptor function in the postmenopausal stage promote neuronal damage and cognitive impairment by exacerbating dyslipidemia, and that estrogen supplementation or lipid lowering is an effective way to ameliorate hippocampal damage and cognitive dysfunction via upregulation of ERs.