Mitochondria-associated ER membranes and Alzheimer disease

作者：Area Gomez Estela; Schon Eric A^*

来源：Current Opinion in Genetics & Development, 2016, 38: 90-96.

DOI：10.1016/j.gde.2016.04.006

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 beta-amyloid (A beta), 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 mitochondria) 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 gamma-secretase activity, which processes the amyloid precursor protein to generate A beta, 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 A beta 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.

• 出版日期2016-6