Estrogen receptor β in Alzheimer's disease: From mechanisms to therapeutics.
Estrogen receptor β in Alzheimer's disease: From mechanisms to therapeutics.
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DOI：
10.1016/j.arr.2015.08.001
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发表时间：
2015-11
影响因子：
13.1
通讯作者：
Chhibber A
中科院分区：
文献类型：
--
作者：
Zhao L;Woody SK;Chhibber A
阿尔茨海默病（AD）对女性和男性都有严重影响。女性对AD的易感性在很大程度上与绝经期卵巢性激素的丢失有关。本文综述了雌激素受体β（ERβ）在神经系统健康调节中的作用及其在AD发生和干预中的意义。自1996年发现以来，在过去的15-20年中进行的研究已经记录了大量证据，表明ERβ在从发育到衰老的广泛大脑活动中起着关键作用。ERβ基因多态性与认知障碍和AD风险增加相关，主要发生在女性。ERβ在AD干预中的作用已通过在转基因模型中响应于ERβ选择性调节剂治疗的AD病理学改变得到证实，所述转基因模型显示出明显的斑块和缠结组织病理学表现以及学习和记忆缺陷。未来的研究，探索ERβ信号和人类载脂蛋白E（APOE）的遗传异构体在脑老化和AD风险表型的发展之间的潜在相互作用是非常必要的。目前AD药物开发中的翻译丢失趋势主要基于早发性家族性AD（FAD）模型，这强调了对概括迟发性散发性AD（SAD）病因学的新型模型的迫切需求，SAD是最常见的AD形式，占当前人类AD人群的95%以上。结合使用FAD相关模型（通常具有良好的表面效度）和SAD相关模型（具有更可靠的结构效度），将共同提高临床前发现成功转化为人类的预测效度。
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.