Estrogen receptor α: a critical role in successful female cognitive aging

Abstract

Due to potential health risks, current recommendations are that individuals who wish to use hormone therapy to treat menopausal symptoms do so for the shortest period of time possible. In our investigation into how short-term use of estrogens in midlife following loss of ovarian function exerts long-term effects on female cognitive aging in rodents, we discovered a link between the ability of previous exposure to estradiol to enhance memory in the long term and its ability to increase estrogen receptor α (ERα) levels in the hippocampus, a brain area important for memory. Follow-up studies in model systems implicate a role for ERα in enhanced cognitive function independent of ovarian or exogenously administered estrogens. Results are consistent with clinical studies in which brain ERα levels in older women and men are related to cognitive functioning and risk of cognitive decline is associated with polymorphisms in the gene that transcribes ERα. Research in preclinical models reveals mechanisms through which ERα can be activated and affect cognition in the absence of ovarian estrogens, including ligand-independent activation via insulin-like growth factor-1 signaling and activation by brain-derived neuroestrogens. This report reviews preclinical and clinical data that collectively point to the importance of ERα in cognition and highlights the need to differentiate the role of estrogen receptors from their classical ligands as we seek approaches to facilitate successful cognitive aging.

摘要

由于潜在的健康风险, 目前的建议是用尽可能短的时间使用激素治疗来治疗绝经症状。本研究旨在探究中年时期卵巢功能丧失后短期使用雌激素如何对雌性啮齿动物的认知衰退产生长期影响。我们发现, 长期使用雌二醇增强记忆的作用与其提高海马中雌激素受体α ( ERα)水平的能力之间存在联系, 海马是大脑中对记忆起重要作用的区域。模型系统的后续研究表明, ERα在增强认知功能方面发挥作用, 独立于卵巢或外源性雌激素。研究结果与临床研究一致, 在这些研究中, 老年女性和男性的大脑ERα水平与认知功能有关, 认知能力下降的风险与转录ERα的基因的多态性有关。临床前模型的研究揭示了ERα在缺乏卵巢雌激素的情况下被激活并影响认知的机制, 包括通过胰岛素样生长因子-1信号转导的配体非依赖性激活和脑源性神经雌激素的激活。这份报告回顾了临床前和临床数据, 这些数据共同指出了ERα在认知中的重要性, 并强调了在我们寻找促进认知衰退途径时, 有必要将雌激素受体的作用与它们的经典配体区分开来。

Keywords:

• Estrogen receptor α
• estrogens
• hippocampus
• brain
• cognition
• aging
• insulin-like growth factor-1
• neuroestrogens
• menopause
• Alzheimer’s disease

Potential conflict of interest

The authors report no conflict of interest. The authors alone are responsible for the content and writing of the article.

Additional information

Funding

Work described in this review that was conducted in our laboratory was supported by the National Institute on Aging [Grant RF1AG041374].