Mitochondria, cholesterol and amyloid β peptide: a dangerous trio in Alzheimer disease
Mitochondria, cholesterol and amyloid β peptide: a dangerous trio in Alzheimer disease
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DOI：
10.1007/s10863-009-9242-6
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发表时间：
2009-10-01
影响因子：
3
通讯作者：
Fernandez-Checa, Jose C.
中科院分区：
文献类型：
--
作者：
Colell, Anna;Fernandez, Anna;Fernandez-Checa, Jose C.
阿尔茨海默病（AD）的分子机制尚未完全了解。来自实验模型的大量证据已经涉及在疾病的发作和进展中毒性淀粉样蛋白β肽（A β）的过度生成和积累。淀粉样蛋白前体蛋白到致病性A β片段的淀粉样蛋白形成加工被认为发生在质膜的特定结构域中，并且受到胆固醇富集的促进。已知细胞内A β积累主要通过线粒体靶向毒性A β诱导氧化应激。最近使用胆固醇负荷小鼠模型的证据表明，由于胆固醇介导的线粒体膜动力学扰动诱导的选择性线粒体GSH（mGSH）耗竭，特异性线粒体胆固醇库使神经元对A β诱导的氧化剂细胞死亡和半胱天冬酶非依赖性细胞凋亡敏感。通过渗透性前体如谷胱甘肽乙酯补充mGSH，保护其免受A β介导的神经毒性和炎症。因此，这些新的数据扩展了胆固醇在AD中的致病作用，表明除了促进A β生成之外，线粒体胆固醇通过mGSH调节决定A β神经毒性。
The molecular mechanisms of Alzheimer's disease (AD) are not fully understood. Extensive evidence from experimental models has involved the overgeneration and accumulation of toxic amyloid beta peptides (A beta) in the onset and progression of the disease. The amyloidogenic processing of amyloid precursor protein into pathogenic A beta fragments is thought to occur in specific domains of the plasma membrane and favored by cholesterol enrichment. Intracellular A beta accumulation is known to induce oxidative stress, predominantly via mitochondria targeting of toxic A beta. Recent evidence using mouse models of cholesterol loading has demonstrated that the specific mitochondrial cholesterol pool sensitizes neurons to A beta-induced oxidant cell death and caspase-independent apoptosis due to selective mitochondrial GSH (mGSH) depletion induced by cholesterol-mediated perturbation of mitochondrial membrane dynamics. mGSH replenishment by permeable precursors such as glutathione ethyl ester protected against A beta-mediated neurotoxicity and inflammation. Thus, these novel data expand the pathogenic role of cholesterol in AD indicating that in addition to fostering A beta generation, mitochondrial cholesterol determines A beta neurotoxicity via mGSH regulation.