Endoplasmic Reticulum Stress Mediates Amyloid β Neurotoxicity via Mitochondrial Cholesterol Trafficking
Endoplasmic Reticulum Stress Mediates Amyloid β Neurotoxicity via Mitochondrial Cholesterol Trafficking
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DOI：
10.1016/j.ajpath.2014.03.014
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发表时间：
2014-07-01
影响因子：
6
通讯作者：
Colell, Anna
中科院分区：
文献类型：
--
作者：
Barbero-Camps, Elisabet;Fernandez, Anna;Colell, Anna
据报道，阿尔茨海默病中胆固醇稳态被破坏，并被认为通过促进淀粉样蛋白P（A β）积累而促进疾病进展。特别是，线粒体胆固醇富集已被证明对A β诱导的神经毒性敏感。然而，阿尔茨海默病中胆固醇水平升高及其向线粒体转运的分子机制仍知之甚少。在这里，我们表明，内质网（ER）的压力引发的A β促进胆固醇合成和胆固醇内流，导致线粒体谷胱甘肽（mGSH）耗尽老年淀粉样前体蛋白/早老素-1（APP/ PS1）小鼠。线粒体胆固醇蓄积与垂体相关的ER膜蛋白表达增加有关，ER膜蛋白有利于胆固醇从ER转运到线粒体，沿着特定的胆固醇载体，特别是类固醇生成急性调节蛋白。在体内治疗与ER应激抑制剂4-苯基丁酸防止线粒体胆固醇负荷和mGSH耗竭，从而保护APP/PS1小鼠对A β诱导的神经毒性。GSH乙酯给药也观察到类似的保护作用，其可抑制mGSH而不影响未折叠蛋白反应，从而将mGSH耗竭定位于ER应激的下游。总体而言，这些结果表明，A β介导的ER应激和增加的线粒体胆固醇运输有助于在老年APP/PS1小鼠中观察到的病理进展，并且ER应激抑制剂可被探索作为阿尔茨海默病的治疗剂。(Am J Pathol 2014，184：2066-2081;
Disrupted cholesterol homeostasis has been reported in Alzheimer disease and is thought to contribute to disease progression by promoting amyloid P (A beta) accumulation. In particular, mitochondrial cholesterol enrichment has been shown to sensitize to A beta-induced neurotoxicity. However, the molecular mechanisms responsible for the increased cholesterol Levels and its trafficking to mitochondria in Alzheimer disease remain poorly understood. Here, we show that endoplasmic reticulum (ER) stress triggered by A beta promotes cholesterol synthesis and mitochondriaL cholesterol influx, resulting in mitochondrial glutathione (mGSH) depletion in older age amyloid precursor protein/presenilin-1 (APP/ PS1) mice. Mitochondria cholesterol accumulation was associated with increased expression of mitochondrial-associated ER membrane proteins, which favor cholesterol transLocation from ER to mitochondria along with specific cholesterol carriers, particularly the steroidogenic acute regulatory protein. In vivo treatment with the ER stress inhibitor 4-phenylbutyric acid prevented mitochondrial cholesterol loading and mGSH depletion, thereby protecting APP/PS1 mice against A beta-induced neurotoxicity. Similar protection was observed with GSH ethyl ester administration, which replenishes mGSH without affecting the unfolded protein response, thus positioning mGSH depletion downstream of ER stress. Overall, these results indicate that A beta-mediated ER stress and increased mitochondria cholesterol trafficking contribute to the pathologic progression observed in old APP/PS1 mice, and that ER stress inhibitors may be explored as therapeutic agents for Alzheimer disease. (Am J Pathol 2014, 184: 2066-2081;