A key role for MAM in mediating mitochondrial dysfunction in Alzheimer disease

Abstract

In the last few years, increased emphasis has been devoted to understanding the contribution of mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) to human pathology in general, and neurodegenerative diseases in particular. A major reason for this is the central role that this subdomain of the ER plays in metabolic regulation and in mitochondrial biology. As such, aberrant MAM function may help explain the seemingly unrelated metabolic abnormalities often seen in neurodegeneration. In the specific case of Alzheimer disease (AD), besides perturbations in calcium and lipid homeostasis, there are numerous documented alterations in mitochondrial behavior and function, including reduced respiratory chain activity and oxidative phosphorylation, increased free radical production, and altered organellar morphology, dynamics, and positioning (especially perinuclear mitochondria). However, whether these alterations are primary events causative of the disease, or are secondary downstream events that are the result of some other, more fundamental problem, is still unclear. In support of the former possibility, we recently reported that C99, the C-terminal processing product of the amyloid precursor protein (APP) derived from its cleavage by β-secretase, is present in MAM, that its level is increased in AD, and that this increase reduces mitochondrial respiration, likely via a C99-induced alteration in cellular sphingolipid homeostasis. Thus, the metabolic disturbances seen in AD likely arise from increased ER-mitochondrial communication that is driven by an increase in the levels of C99 at the MAM.

Targeting mitochondria‐associated membranes as a potential therapy against endothelial injury induced by hypoxia

“…Therefore, MAMs are involved in steroid synthesis, phospholipid metabolism, autophagy, inflammation and mitochondrial bioenergetics. Recent studies have described the important role of MAMs in the pathogenesis of several diseases such as senescence, Alzheimer's disease, obesity and myocardial ischemia‐reperfusion . However, the role of MAMs in hypoxia‐induced mitochondrial impairment and injury in ECs remains unclear.…”

“…Recent studies have described the important role of MAMs in the pathogenesis of several diseases such as senescence, Alzheimer's disease, obesity and myocardial ischemia-reperfusion. [20][21][22][23] However, the role of MAMs in hypoxia-induced mitochondrial impairment and injury in ECs remains unclear.…”

Ca2+homeostasis dysregulation in Alzheimer's disease: a focus on plasma membrane and cell organelles

“…In AD pathogenesis, enhanced Ca 2+ transfer from ER to mitochondria leads to decreased ATP production, elevated ROS generation, and the activation of apoptosis (212)(213)(214). It has been reported that deficiency or inhibition of CypD can rescue the mitochondrial dysfunction and synaptic degeneration from Ab toxicity (215)(216)(217), which demonstrates mPTP's contribution to AD pathogenesis and suggests its potential role as a therapeutic target.…”

Adeno‐associated virus‐based Alzheimer's disease mouse models and potential new therapeutic avenues

“…The prevailing theory for AD pathogenesis remains the amyloid cascade hypothesis that states Aβ accumulation, due to its increased formation or its decreased clearance (Mawuenyega et al, ), as the disease‐initiating event (see Hardy & Selkoe, ). However, there are a number of alternative or complementing theories that have been put forward over time (Area‐Gomez et al, ; Atwood & Bowen, ; Bloom, ; Friedland‐Leuner, Stockburger, Denzer, Eckert, & Muller, ; Leuner et al, ).…”

“…However, there are a number of alternative or complementing theories that have been put forward over time (Area-Gomez et al, 2018;Atwood & Bowen, 2015;Bloom, 2014;Friedland-Leuner, Stockburger, Denzer, Eckert, & Muller, 2014;Leuner et al, 2007).…”