雌激素神经元保护作用的相关机制

摘要/Abstract

摘要： 阿尔茨海默病（Alzheimer's disease，AD）是一种中枢神经系统退行性疾病，主要表现为β-淀粉样蛋白（Beta amyloid protein，Aβ）的沉积和神经纤维的缠结，而且女性的发病率明显高于男性。目前认为AD的发生和发展与雌激素的减少密切相关，然而，雌激素的神经保护作用机制尚不明确。研究发现雌激素可与其受体结合，调节Trx-1和Ask-1的活性，抑制死亡结构域相关蛋白（Death domain associate protein，Daxx）向细胞质转移，阻断Ask-1/JNK信号转导途径从而发挥抗氧化应激和凋亡；激活MAPK/ERK信号途径，促进淀粉前体蛋白（Amyloid precursor protein，APP）的非淀粉源途径，阻止Aβ的形成；此外，研究还发现被活化的雌激素受体与小窝蛋白相互作用，激活代谢型谷氨酸受体（metabotropic glutamate receptors，mGluRs），促进环磷腺苷效应元件结合蛋白（cAMP-response element binding protein，CREB）磷酸化；介导第二信使对抗谷氨酸的神经兴奋毒性而发挥神经保护作用。本文将对雌激素发挥神经保护作用的具体机制进行总结分析，为AD的预防和治疗提供一定的理论基础。

关键词: 雌激素, 雌激素受体, 阿尔茨海默病, 死亡结构域相关蛋白, 小窝蛋白

Abstract: Alzheimer’s disease(AD) is a neurodegenerative disease of the central nervous system, which is characterized by deposition of amyloid beta(Aβ) and neurofibrillary tangles and the incidence of women significantly higher than men. The studies have shown that the occurrence and development of AD are closely associated with the declining estrogen levels, however, the mechanism underlying estrogen’s neuroprotective effect is not fully clarified. The study found that when estrogen bind to its receptor, it can regulate the activity of Trx-1 and Ask-1, inhibit the cytosolic translocation of Death domain associate protein(Daxx), block the Ask-1/JNK signal transduction pathway to exert against oxidative stress and apoptosis; Estrogen organizes ER to activate MAPK/ERK signaling pathway to promote the non-amyloidogenic pathway of Amyloid precursor protein(APP) which is prevent the formation of Aβ; In addition, the research also found that the activated estrogen receptors interaction with caveolin proteins to activate metabotropic glutamate receptors(mGluRs) which induces cAMP-response element binding protein(CREB) phosphorylation; It mediates second messenger to protect against glutamate excitotoxicity so as to exert neuroprotective effect. In this review, the potential mechanisms of estrogen’s neuroprotective effect are reviewed, in order to provide theoretical basis for the prevention and treatment of AD.

Key words: estrogen, estrogen receptor, Alzheimer&, rsquo, s disease, Death domain associate protein, caveolin proteins

钟明，沈丽霞. 雌激素神经元保护作用的相关机制[J]. 神经药理学报, 2015, 5(2): 54-64.

ZHONG Ming, SHEN Li-Xia. Study of the Mechanism of Estrogen on Neuroprotective Effect[J]. Acta Neuropharmacologica, 2015, 5(2): 54-64.

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