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ApoE2,ApoE3和ApoE4不同刺激APP转录和Aβ分泌

Yu-Wen Alvin Huang¹, Bo Zhou², Marius Wernig³

¹Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University Medical School, Stanford, CA 94305, USA.

|January 24, 2017

概括

通过刺激神经元中的粉样β (Aβ) 生产,Apolipoprotein E4 (ApoE4) 显著增加了阿尔茨海默病的风险. 这通过一种新的信号通路发生,涉及双素-拉链激酶 (DLK) 激活.

科学领域:

神经科学
遗传学
分子生物学

背景情况:

人类的阿波利波蛋白E (ApoE) 有三种异型:ApoE2,ApoE3和ApoE4.
ApoE4是阿尔茨海默病 (AD) 的主要遗传风险因素,而ApoE2是保护性的,ApoE3是中性的.
通过ApoE异型影响AD病变的确切机制尚未完全理解.

研究的目的:

阐明ApoE异型对神经元中的粉样β (Aβ) 生产产生影响的分子机制.
确定参与阿波E介导的粉样前体蛋白 (APP) 转录的信号通路.

主要方法:

使用胚胎干细胞 (ES) 来源的人类神经元.
研究了神经质分泌的ApoE异型对神经元Aβ产生的影响.
检查了双素-拉链激酶 (DLK) 和下游MAP激酶 (MKK7,ERK1/2) 的激活.
评估AP-1转录因子在调节APP转录中的作用.

主要成果:

质衍生的ApoE刺激神经元Aβ的产生,其强度为ApoE4> ApoE3> ApoE2.
ApoE与神经元受体结合激活了DLK/MKK7/ERK1/2 MAP激酶级联.
激活的ERK1/ 2导致cFos酸化和AP-1激活.
AP-1 增强了 APP 转录,增加了 Aβ 水平.
这种机制在小鼠中得到证实.

结论:

在神经元中发现了一种新的信号传导途径,ApoE异型调节APP转录和Aβ合成.
作为AD风险因素的ApoE4异型与其强烈激活这一途径有关.
了解这种途径为阿尔茨海默病提供了潜在的治疗点.

关键词:

一个APP 阿尔茨海默病美国美国关于CRISPR的研究在CRISPRi中 DLK 的 MAP 激酶信号传递粉样蛋白前体蛋白脂蛋白E 贝塔粉样蛋白 cFos 其他双氨酸-拉链激酶转录

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