Estrogen receptors and the aging brain

Abstract

The female sex hormone estrogen has been ascribed potent neuroprotective properties. It signals by binding and activating estrogen receptors that, depending on receptor subtype and upstream or downstream effectors, can mediate gene transcription and rapid non-genomic actions. In this way, estrogen receptors in the brain participate in modulating neural differentiation, proliferation, neuroinflammation, cholesterol metabolism, synaptic plasticity, and behavior. Circulating sex hormones decrease in the course of aging, more rapidly at menopause in women, and slower in men. This review will discuss what this drop entails in terms of modulating neuroprotection and resilience in the aging brain downstream of spatiotemporal estrogen receptor alpha (ERα) and beta (ERβ) signaling, as well as in terms of the sex differences observed in Alzheimer’s disease (AD) and Parkinson’s disease (PD). In addition, controversies related to ER expression in the brain will be discussed. Understanding the spatiotemporal signaling of sex hormones in the brain can lead to more personalized prevention strategies or therapies combating neurodegenerative diseases.

Fetal origin of sex‐bias brain aging

“…Multiple studies have shown that exposure to sex hormone at the fetal stage plays a leading role in sex‐specific fetal programming of cellular metabolism that poses a differential risk to metabolic diseases later in life, 92,93 including a metabolic decline of the brain 12 . In particular, the regulation of estrogen receptors (ERs) and orphan estrogen‐related receptors (ERRs) plays important functions in brain aging 94,95 . Our data (Supporting Information Table S4) showed that ERR‐alpha ( Esrra ) was expressed at a higher level compared to Esr1, Esr2, Essrb , and Essrg in the brain at all stages (fetal, postnatal, and aging) of the mice.…”

“…12 In particular, the regulation of estrogen receptors (ERs) and orphan estrogen-related receptors (ERRs) plays important functions in brain aging. 94,95 Our data (Supporting Information Table S4) showed that ERR-alpha (Esrra) was expressed at a higher level compared to Esr1, Esr2, Essrb, and Essrg in the brain at all stages (fetal, postnatal, and aging) of the mice. The WGBS data showed that Esrra remained unmethylated while Esr1, Esr2, Essrb, and Essrg were methylated in the brain.…”

Biological Brain Age Prediction Using Machine Learning on Structural Neuroimaging Data: Multi-Cohort Validation Against Biomarkers of Alzheimer’s Disease and Neurodegeneration stratified by sex

“…These results were expected, as females have higher chances of developing neurodegeneration and have showed to undergo faster cognitive decline than males (Ferretti et al, 2018). Although the role of sex hormones still needs to be clarified, it has been suggested that the menopausal drop of estrogen increases vulnerability to neurological events (Green & Simpkins, 2000; Maioli et al, 2021). On the contrary, results suggest that morphological effects of aging in the CU males’ brain are not fully driven by neurodegeneration, although these effects might increase with older age in MCI males.…”

Ovarian steroid hormones: A long overlooked but critical contributor to brain aging and Alzheimer’s disease

“…As reviewed below, estradiol receptors (chiefly ERα and ERβ) are present throughout areas of the brain involved in both reproductive and cognitive functions ( McEwen et al, 2001 ). However, there is controversy regarding estrogen receptor expression across species, especially ERβ, due to limited ERβ antibody specificity ( Maioli et al, 2021 ). Validated techniques have confirmed ERβ in rodent but not human brain ( Maioli et al, 2021 ).…”