Area-Gomez Estela, Schon Eric A
Department of Neurology, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA.
Department of Genetics and Development, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA.
Adv Exp Med Biol. 2017;997:149-156. doi: 10.1007/978-981-10-4567-7_11.
The most widely accepted hypothesis to explain the pathogenesis of Alzheimer disease (AD) is the amyloid cascade, in which the accumulation of extraneuritic plaques and intracellular tangles plays a key role in driving the course and progression of the disease. However, there are other biochemical and morphological features of AD, including altered calcium, phospholipid, and cholesterol metabolism and altered mitochondrial dynamics and function that often appear early in the course of the disease, prior to plaque and tangle accumulation. Interestingly, these other functions are associated with a subdomain of the endoplasmic reticulum (ER) called mitochondria-associated ER membranes (MAM). MAM, which is an intracellular lipid raft-like domain, is closely apposed to mitochondria, both physically and biochemically. These MAM-localized functions are, in fact, increased significantly in various cellular and animal models of AD and in cells from AD patients, which could help explain the biochemical and morphological alterations seen in the disease. Based on these and other observations, a strong argument can be made that increased ER-mitochondria connectivity and increased MAM function are fundamental to AD pathogenesis.
解释阿尔茨海默病（AD）发病机制最被广泛接受的假说是淀粉样蛋白级联反应，其中细胞外斑块和细胞内缠结的积累在推动疾病的进程和发展中起关键作用。然而，AD还有其他生化和形态学特征，包括钙、磷脂和胆固醇代谢改变以及线粒体动力学和功能改变，这些特征常在疾病进程早期出现，早于斑块和缠结的积累。有趣的是，这些其他功能与内质网（ER）的一个亚结构域有关，称为线粒体相关内质网膜（MAM）。MAM是一种细胞内脂筏样结构域，在物理和生化方面都与线粒体紧密相邻。事实上，在AD的各种细胞和动物模型以及AD患者的细胞中，这些MAM定位的功能显著增加，这有助于解释在该疾病中看到的生化和形态学改变。基于这些及其他观察结果，可以有力地论证，内质网 - 线粒体连接性增加和MAM功能增强是AD发病机制的基础。
