Sex-Specific Regulation of β-Secretase: A Novel Estrogen Response Element (ERE)-Dependent Mechanism in Alzheimer's Disease

Women have a higher prevalence and incidence of Alzheimer's disease (AD) than age-matched men, and loss of estrogen might be partially responsible for the higher risk of AD in aged women. While β-secretase (BACE1) plays an important role in AD pathogenesis, whether BACE1 involved the sex difference in AD pathology remains unclear. This study investigated the hypothesis that estrogen regulates BACE1 transcription via the estrogen response element (ERE) and designated pathways. Using estrogen receptor (ER) knock-out mice and mutagenesis of EREs in HEK293 cells, we demonstrated sex-specific inhibition of BACE1 transcription by estrogen via direct binding to ERE sites and ERα. We also used a repressor of estrogen receptor activity (REA) and showed that an REA-ERE complex downregulated BACE1. A chromatin immunoprecipitation assay analysis determined that all three EREs at the BACE1 promoter were required for estradiol-mediated downregulation of BACE1 transcription in mice. Last, we confirmed the impairment of the REA pathway in the cortex of female AD patients. Our study identified an estrogen-specific BACE1 transcriptional regulation pathway from cell and animal models to AD patients.SIGNIFICANCE STATEMENT With the increase in the aging population and Alzheimer's disease worldwide, an urgent need to find effective approaches to treat or prevent AD. Women have a higher prevalence and incidence of AD than men. Identification of the sex-specific risk for AD may be valuable for disease prevention. This study evaluated several estrogen response element (ERE) sites on the promoter of β-secretase (BACE1), a key enzyme for AD pathology. We demonstrated that estrogen downregulated BACE1 transcription through direct binding and complex formation with ERE and cofactors. Our novel findings provide evidence that an estrogen supplement may decrease the risk of AD in menopausal and postmenopausal women. Furthermore, this study demonstrates the "sex-specific" mechanisms of BACE1 as a role in AD pathogenesis.