Estrogen receptor β in Alzheimer’s disease: From mechanisms to therapeutics

Abstract

Alzheimer's disease (AD) disproportionally affects women and men. The female susceptibility for AD has been largely associated with the loss of ovarian sex hormones during menopause. This review examines current understanding of the role of estrogen receptor β (ERβ) in the regulation of neurological health and its implication in the development and intervention of AD. Since its discovery in 1996, research conducted over the last 15-20 years has documented a great deal of evidence indicating that ERβ plays a pivotal role in a broad spectrum of brain activities from development to aging. ERβ genetic polymorphisms have been associated with cognitive impairment and increased risk for AD predominantly in women. The role of ERβ in the intervention of AD has been demonstrated by the alteration of AD pathology in response to treatment with ERβ-selective modulators in transgenic models that display pronounced plaque and tangle histopathological presentations as well as learning and memory deficits. Future studies that explore the potential interactions between ERβ signaling and the genetic isoforms of human apolipoprotein E (APOE) in brain aging and development of AD-risk phenotype are critically needed. The current trend of lost-in-translation in AD drug development that has primarily been based on early-onset familial AD (FAD) models underscores the urgent need for novel models that recapitulate the etiology of late-onset sporadic AD (SAD), the most common form of AD representing more than 95% of the current human AD population. Combining the use of FAD-related models that generally have excellent face validity with SAD-related models that hold more reliable construct validity would together increase the predictive validity of preclinical findings for successful translation into humans.

Towards Personalized Intervention for Alzheimer’s Disease

“…It has been postulated that decreased estrogen levels at old age may be partially responsible for higher incidence of AD in females [18]. Estrogen is neuroprotective and estrogen receptor β plays a critical role in brain function [19]. Studies on the human brain transcriptome have also shown that immune response is more widely spread in aged female brains than aged male brains, consistent with the accelerated aging scenario in female brains [20].…”

New Insights for Hormone Therapy in Perimenopausal Women Neuroprotection

“…Recent studies are involving the genetic polymorphism of ERs, especially of ER-β in cognitive impairment and increased risk for AD predominantly in women [106]. It was examined that the role of single nucleotide polymorphisms (SNP) in the ERs genes: rs9340799, rs2234693, rs2228480 (in the ESR1 gene), and rs4986938 (in the ESR2 gene) as a risk factor for amnesic mild cognitive impairment (MCI) and AD.…”

Management of Alzheimers Disease: Role of Existing Therapies, Traditional Medicines and New Treatment Targets

“…Additional properties of oestrogens, which may contribute to their neuroprotective effects include antioxidant properties and a facilitation of the processing of APP along a non-amyloidogenic pathway [42] . Oestrogen receptor β (ERβ) has shown to have the role in regulation of neurological health and development of AD though the therapeutic role is yet unclear as it lacks evidence in humans [41] .…”

“…Oestrogens are shown to have protective effects on hippocampal dendrites with augmentation of choline acetyl-transferase activity in experimental studies [41] . Additional properties of oestrogens, which may contribute to their neuroprotective effects include antioxidant properties and a facilitation of the processing of APP along a non-amyloidogenic pathway [42] .…”