Wang Xinyi, Feng Shu, Deng Qianting, Wu Chongyun, Duan Rui, Yang Luodan
Laboratory of Exercise and Neurobiology, School of Physical Education and Sports Science, South China Normal University, Guangzhou, 510006, China.
Laboratory of Regenerative Medicine in Sports Science, School of Physical Education and Sports Science, South China Normal University, Guangzhou, China.
Mol Cell Biochem. 2025 Apr;480(4):1983-1998. doi: 10.1007/s11010-024-05071-4. Epub 2024 Aug 1.
Estrogens are pivotal regulators of brain function throughout the lifespan, exerting profound effects from early embryonic development to aging. Extensive experimental evidence underscores the multifaceted protective roles of estrogens on neurons and neurotransmitter systems, particularly in the context of Alzheimer's disease (AD) pathogenesis. Studies have consistently revealed a greater risk of AD development in women compared to men, with postmenopausal women exhibiting heightened susceptibility. This connection between sex factors and long-term estrogen deprivation highlights the significance of estrogen signaling in AD progression. Estrogen's influence extends to key processes implicated in AD, including amyloid precursor protein (APP) processing and neuronal health maintenance mediated by brain-derived neurotrophic factor (BDNF). Reduced BDNF expression, often observed in AD, underscores estrogen's role in preserving neuronal integrity. Notably, hormone replacement therapy (HRT) has emerged as a sex-specific and time-dependent strategy for primary cardiovascular disease (CVD) prevention, offering an excellent risk profile against aging-related disorders like AD. Evidence suggests that HRT may mitigate AD onset and progression in postmenopausal women, further emphasizing the importance of estrogen signaling in AD pathophysiology. This review comprehensively examines the physiological and pathological changes associated with estrogen in AD, elucidating the therapeutic potential of estrogen-based interventions such as HRT. By synthesizing current knowledge, it aims to provide insights into the intricate interplay between estrogen signaling and AD pathogenesis, thereby informing future research directions and therapeutic strategies for this debilitating neurodegenerative disorder.
雌激素是整个生命周期中脑功能的关键调节因子，从早期胚胎发育到衰老都发挥着深远影响。大量实验证据强调了雌激素对神经元和神经递质系统的多方面保护作用，尤其是在阿尔茨海默病（AD）发病机制的背景下。研究一直表明，与男性相比，女性患AD的风险更高，绝经后女性的易感性更高。性别因素与长期雌激素缺乏之间的这种联系凸显了雌激素信号在AD进展中的重要性。雌激素的影响延伸到AD相关的关键过程，包括淀粉样前体蛋白（APP）的加工以及由脑源性神经营养因子（BDNF）介导的神经元健康维持。在AD中经常观察到BDNF表达降低，这凸显了雌激素在维持神经元完整性方面的作用。值得注意的是，激素替代疗法（HRT）已成为一种针对原发性心血管疾病（CVD）预防的性别特异性和时间依赖性策略，对AD等与衰老相关的疾病具有良好的风险特征。有证据表明，HRT可能减轻绝经后女性AD的发病和进展，进一步强调了雌激素信号在AD病理生理学中的重要性。本综述全面研究了AD中与雌激素相关的生理和病理变化，阐明了基于雌激素的干预措施（如HRT）的治疗潜力。通过综合现有知识，旨在深入了解雌激素信号与AD发病机制之间的复杂相互作用，从而为这种使人衰弱的神经退行性疾病的未来研究方向和治疗策略提供信息。
