Mitochondria-associated ER membranes and Alzheimer disease.
Mitochondria-associated ER membranes and Alzheimer disease.
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DOI：
10.1016/j.gde.2016.04.006
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发表时间：
2016-06
影响因子：
4
通讯作者：
Schon EA
中科院分区：
文献类型：
--
作者：
Area-Gomez E;Schon EA
阿尔茨海默病（Alzheimer disease，AD）的发病机制尚不清楚.最被广泛接受的假说称为淀粉样蛋白级联反应，其基于以下观察结果：AD患者的大脑含有高水平的细胞外斑块（主要由β-淀粉样蛋白（Aβ）组成）和细胞内缠结（由微管相关蛋白tau的过度磷酸化形式组成）。然而，AD还具有其他特征，包括异常的胆固醇、磷脂和钙代谢以及线粒体功能障碍，所有这些表面上与斑块和缠结形成无关。值得注意的是，AD病理学的这些“其他”方面是与线粒体相关的ER膜（MAM）相关的功能，MAM是内质网（ER）的与线粒体并置并与其通信的亚结构域。鉴于MAM和AD之间的潜在关系，我们探讨了MAM功能紊乱可能在AD发病机制中发挥作用的可能性。我们发现，γ-分泌酶活性，其加工淀粉样前体蛋白以产生Aβ，主要位于MAM中，并且在AD患者的细胞中ER-线粒体沉积和MAM功能显著增加。这些观察结果可能不仅有助于解释异常Aβ的产生，还有助于解释该疾病的许多“其他”生化和形态学特征。基于这些和其他数据，我们提出AD从根本上说是一种ER-线粒体超连接性疾病。
The series of events underlying the pathogenesis of Alzheimer disease (AD) in unknown. The most widely-accepted hypothesis is called the amyloid cascade, based on the observation that the brains of AD patients contain high levels of extracellular plaques, composed mainly of β-amyloid (Aβ), and intracellular tangles, composed of hyperphosphorylated forms of the microtubule-associated protein tau. However, AD is also characterized by other features, including aberrant cholesterol, phospholipid, and calcium metabolism, and mitochondrial dysfunction, all ostensibly unrelated to plaque and tangle formation. Notably, these “other” aspects of AD pathology are functions related to mitochondria-associated ER membranes (MAM), a subdomain of the endoplasmic reticulum (ER) that is apposed to, and communicates with, mitochondria. Given the potential relationship between MAM and AD, we explored the possibility that perturbed MAM function might play a role in AD pathogenesis. We found that γ-secretase activity, which processes the amyloid precursor protein to generate Aβ, is located predominantly in the MAM, and that ER-mitochondrial apposition and MAM function are increased significantly in cells from AD patients. These observations may help explain not only the aberrant Aβ production, but also many of the “other” biochemical and morphological features of the disease. Based on these, and other, data we propose that AD is fundamentally a disorder of ER-mitochondrial hyperconnectivity.