Area-Gomez Estela, Schon Eric A
Department of Neurology, Columbia University, New York, New York, USA; and
Department of Neurology, Columbia University, New York, New York, USA; and.
FASEB J. 2017 Mar;31(3):864-867. doi: 10.1096/fj.201601309.
The pathogenesis of Alzheimer's disease (AD) is currently unclear and is the subject of much debate. The most widely accepted hypothesis designed to explain AD pathogenesis is the amyloid cascade, which invokes the accumulation of extracellular plaques and intracellular tangles as playing a fundamental role in the course and progression of the disease. However, besides plaques and tangles, other biochemical and morphological features are also present in AD, often manifesting early in the course of the disease before the accumulation of plaques and tangles. These include altered calcium, cholesterol, and phospholipid metabolism; altered mitochondrial dynamics; and reduced bioenergetic function. Notably, these other features of AD are associated with functions localized to a subdomain of the endoplasmic reticulum (ER), known as mitochondria-associated ER membranes (MAMs). The MAM region of the ER is a lipid raft-like domain closely apposed to mitochondria in such a way that the 2 organelles are able to communicate with each other, both physically and biochemically, thereby facilitating the functions of this region. We have found that MAM-localized functions are increased significantly in cellular and animal models of AD and in cells from patients with AD in a manner consistent with the biochemical findings noted above. Based on these and other observations, we propose that increased ER-mitochondrial apposition and perturbed MAM function lie at the heart of AD pathogenesis.-Area-Gomez, E., Schon, E. A. On the pathogenesis of Alzheimer's disease: the MAM hypothesis.
阿尔茨海默病（AD）的发病机制目前尚不清楚，是众多争论的焦点。为解释AD发病机制而提出的最广泛接受的假说是淀粉样蛋白级联反应，该假说认为细胞外斑块和细胞内缠结的积累在疾病的进程和发展中起基本作用。然而，除了斑块和缠结外，AD还存在其他生化和形态学特征，这些特征在疾病进程中往往在斑块和缠结积累之前就已出现。这些特征包括钙、胆固醇和磷脂代谢改变；线粒体动力学改变；以及生物能量功能降低。值得注意的是，AD的这些其他特征与内质网（ER）一个亚结构域的功能有关，该亚结构域称为线粒体相关内质网膜（MAMs）。内质网的MAM区域是一个脂质筏样结构域，与线粒体紧密相邻，使得这两个细胞器能够在物理和生化方面相互交流，从而促进该区域的功能。我们发现，在AD的细胞和动物模型以及AD患者的细胞中，MAM定位的功能显著增加，其方式与上述生化发现一致。基于这些及其他观察结果，我们提出内质网与线粒体的附着增加以及MAM功能紊乱是AD发病机制的核心。——阿雷亚 - 戈麦斯，E.，舍恩，E. A. 关于阿尔茨海默病的发病机制：MAM假说
