Mitochondria-associated ER membranes and Alzheimer disease

Abstract

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.

Figure 1. Amyloidogenic processing of APP

Consecutive cleavages of APP, a membrane-tethered protein (shaded box), by BACE1 (to produce C99 and soluble APPβ) and γ-secretase (containing PS1 or PS2) generate Aβ and the APP intracellular domain (AICD).

Figure 2. The amyloid cascade hypothesis

Aberrant APP processing gives rise to plaques and then tangles (reproduced from [71], with permission). See text for details.

Figure 3. Other features of Alzheimer disease

Besides plaques and tangles [71], AD is also characterized by perturbations in calcium homeostasis, cholesterol metabolism, phospholipid metabolism, and dynamics and function of mitochondria [72].

Figure 4. The MAM hypothesis

The hypothesis proposes that the functional cause of AD is upregulated ER-mitochondria communication at the MAM. This results in alterations in the indicated functions, as well as an increase in the Aβ₄₂:Aβ₄₀ ratio; the plaques and tangles arise as a downstream result of that perturbation. The increased ER-mitochondrial connectivity is the result of a derangement in specific biochemical pathways brought on by mutations in PS’s and APP (in the case of FAD) or by other causes (in the case of SAD).