Estrogen Stimulates Degradation of β-Amyloid Peptide by Up-regulating Neprilysin
Estrogen Stimulates Degradation of β-Amyloid Peptide by Up-regulating Neprilysin
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雌激素通过上调脑啡肽酶刺激β-淀粉样肽的降解
DOI：
10.1074/jbc.m109.051664
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发表时间：
2010-01-08
影响因子：
4.8
通讯作者：
Huang, Jian
中科院分区：
文献类型：
--
作者：
Liang, Kaiwei;Yang, Liuqing;Huang, Jian
绝经后雌激素耗竭是阿尔茨海默病（AD）的特征性风险因素，AD是一种与脑组织中高水平β-淀粉样肽（A β）相关的人类疾病。以前的研究表明，雌激素负调节大脑中A β的水平，但分子机制尚不清楚。在这里，我们提供的证据表明，雌激素促进A β降解主要是通过一个主要的A β降解酶，脑啡肽酶，在神经母细胞瘤SH-SY 5 Y细胞。我们还表明，由雌激素的脑啡肽酶的上调是依赖于雌激素受体α和β（ER α和ER β），和配体激活的ER调节脑啡肽酶的表达，通过ER和雌激素反应元件（ERE）之间的物理相互作用在脑啡肽酶基因中确定。这些结果证实了在体外凝胶位移和在体内染色质免疫沉淀分析，这表明特异性结合的ER α和ER β的两个推定的ERE在脑啡肽酶基因。在酵母模型系统中，ERE还增强ER α-和ER β-依赖性报告基因表达。因此，本文描述的研究提供了一种推定的机制，通过该机制雌激素正调控脑啡肽酶的表达以促进A β的降解，从而降低AD的风险。这些结果可能会导致新的方法来预防或治疗AD。
Postmenopausal estrogen depletion is a characterized risk factor for Alzheimer disease (AD), a human disorder linked to high levels of beta-amyloid peptide (A beta) in brain tissue. Previous studies suggest that estrogen negatively regulates the level of A beta in the brain, but the molecular mechanism is unknown. Here, we provide evidence that estrogen promotes A beta degradation mainly through a principal A beta degrading enzyme, neprilysin, in neuroblastoma SH-SY5Y cells. We also demonstrate that up-regulation of neprilysin by estrogen is dependent on both estrogen receptor alpha and beta (ER alpha and ER beta), and ligand-activated ER regulates expression of neprilysin through physical interactions between ER and estrogen response elements (EREs) identified in the neprilysin gene. These results were confirmed by in vitro gel shift and in vivo chromatin immunoprecipitation analyses, which demonstrate specific binding of ER alpha and ER beta to two putative EREs in the neprilysin gene. The EREs also enhance ER alpha- and ER beta-dependent reporter gene expression in a yeast model system. Therefore, the study described here provides a putative mechanism by which estrogen positively regulates expression of neprilysin to promote degradation of A beta, reducing risk for AD. These results may lead to novel approaches to prevent or treat AD.