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- W2896912898 abstract "Epidemiological studies have posited an inverse correlation between estrogen levels and the risk for Alzheimer's disease (AD). Furthermore, estrogen replacement therapy (ERT) in postmenopausal women is associated with improvements in cognition, executive function, and memory and negatively correlated with the degree of dementia. A multitude of laboratory studies have demonstrated that 17β-estradiol, the most abundant endogenous estrogen, decreases Amyloid-β (Aβ) burden and improves cognition as well as rescues learning and memory deficits in a host of transgenic mouse models of AD. Furthermore, 17β-estradiol has been shown to attenuate Aβ genesis, Aβ fibrillation, and Aβ-induced cell death in a plethora primary and immortalized cell culture models. Despite overwhelming evidence implicating the role of estrogens in the pathogenesis of AD, the underlying molecular mechanisms and signaling cascades involved in the neuroprotective effects of 17β-estradiol have not been exhaustively elucidated. Herein, we determined the effects of 17β-estradiol on the transcriptional regulation of BACE1, the enzyme that catalyzes the rate limiting step in Aβ genesis. We further characterized and delineated the molecular mechanisms that underlie the effects of 17β-estradiol on BACE1 transcriptional regulation. The effects of 17β-estradiol on BACE1 expression and enzymatic activity were determined in human SH-SY5Y neuroblastoma cells stably expressing the AβPP Swedish KM670/671NL double mutation (SH-SY5Y-APPSwe). We further determined the role of Estrogen Receptor alpha (ERα) and Estrogen Receptor beta (ERβ) in mediating the effects of 17β-estradiol. Our results unequivocally show the 17β-estradiol attenuates basal BACE1 expression and activity leading to a decrease in the basal intracellular and secreted Aβ. The characterization of the molecular mechanisms showed that the 17β-estradiol induced attenuation in BACE1 expression were contingent on ERα transcriptional activity, but independent of ERβ transcriptional activity. Further delineation of the molecular mechanisms showed that 17β-estradiol induced ERα activation trans-represses NF-κB driven constitutive BACE1 expression. Our study identifies a novel signaling pathway and provides a mechanistic insight into the molecular players involved in the effects of 17β-estradiol on the transcriptional repression of basal BACE1 expression." @default.
- W2896912898 created "2018-10-26" @default.
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- W2896912898 date "2018-07-01" @default.
- W2896912898 modified "2023-10-16" @default.
- W2896912898 title "P1‐184: ESTRADIOL REDUCES BASAL BACE1 EXPRESSION THROUGH THE ACTIVATION OF ESTROGEN RECEPTOR ALPHA" @default.
- W2896912898 doi "https://doi.org/10.1016/j.jalz.2018.06.188" @default.
- W2896912898 hasPublicationYear "2018" @default.
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