Mitochondria-associated membranes (MAMs): a potential therapeutic target for treating Alzheimer’s disease

Abstract

Alzheimer's disease (AD), a progressive neurodegenerative disorder, is a leading global health concern for individuals and society. However, the potential mechanisms underlying the pathogenesis of AD have not yet been elucidated. Currently, the most widely acknowledged hypothesis is amyloid cascade owing to the brain characteristics of AD patients, including great quantities of extracellular β-amyloid (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). Nevertheless, the amyloid cascade hypothesis cannot address certain pathologies that precede Aβ deposition and NFTs formation in AD, such as aberrant calcium homeostasis, abnormal lipid metabolism, mitochondrial dysfunction and autophagy. Notably, these earlier pathologies are closely associated with mitochondria-associated membranes (MAMs), the physical structures connecting the endoplasmic reticulum (ER) and mitochondria, which mediate the communication between these two organelles. It is plausible that MAMs might be involved in a critical step in the cascade of earlier events, ultimately inducing neurodegeneration in AD. In this review, we focus on the role of MAMs in the regulation of AD pathologies and the potential molecular mechanisms related to MAM-mediated pathological changes in AD. An enhanced recognition of the preclinical pathogenesis in AD could provide new therapeutic strategies, shifting the modality from treatment to prevention.

Axonal generation of amyloid-β from palmitoylated APP in mitochondria-associated endoplasmic reticulum membranes

“…The mechanisms in the early phase leading to axonal damage in AD pathology remain unclear. MAM dysregulation is an early event in AD pathogenesis (for review, see Yu et al, 2021 ). Axonal BACE1 levels were increased in axonal swellings in an AD mouse model by genetic deletion of an adaptor protein GGA3, which regulates lysosomal degradation of BACE1, leading to increased production of Aβ ( Lomoio et al, 2020 ).…”

Structure and Function of Mitochondria-Associated Endoplasmic Reticulum Membranes (MAMs) and Their Role in Cardiovascular Diseases

“…Later on, Poston et al identified 1212 candidates, including weak soluble proteins at the MAM [21]. Until now, various proteins (approximately 1000) localized within the MAMs were identified in the brain and liver with the aid of in-depth mass spectrometry analysis [22]. Above all, the components within MAMs were highly conserved among species and tissues.…”

ATP Synthase and Mitochondrial Bioenergetics Dysfunction in Alzheimer’s Disease

“…In fact, as previously mentioned, mitochondria have been shown to be a direct site for the accumulation of aggregated Aβ in the neurons of both animal models of AD and samples obtained from patients of the disease. One of the mechanisms that can explain the cytotoxicity of the peptide involves the mechanisms of the calcium transfer from ER to mitochondria, which has been demonstrated in various models of AD [ 142 , 143 , 144 , 145 ]. Specifically, Boyman et al showed that the content of the mitochondrial calcium uniporter (MCU), a structure that allows calcium to flow from the ER to mitochondria [ 146 ], significantly increases in fibroblasts obtained from AD patients, when compared with healthy age-matched individuals [ 147 ].…”

“…The interaction between mitochondria and ER in mammalian cells is mediated by the mitochondria-associated ER membranes (MAMs) [ 148 ]. MAMs play a crucial role not only in calcium homeostasis but also in the regulation of lipid synthesis, mitochondrial dynamics, energy metabolism, cell survival, and apoptotic signaling [ 142 , 145 ]. Interestingly, using mammalian cells, Area-Gomez et al demonstrated that in AD models there is an upregulation of MAM activity, which elevates the crosstalk between mitochondria and ER, deleteriously affecting mitochondrial calcium homeostasis [ 149 ].…”

“…Interestingly, using mammalian cells, Area-Gomez et al demonstrated that in AD models there is an upregulation of MAM activity, which elevates the crosstalk between mitochondria and ER, deleteriously affecting mitochondrial calcium homeostasis [ 149 ]. Moreover, the upregulation of MAM-associated proteins, which increases the number of ER-mitochondria contact points, as well as the MAM-associated protein expression in the primary hippocampal neurons extracted from postmortem human samples from AD patients and from transgenic models of the diseases, has also been demonstrated [ 142 , 145 ]. These effects were observed even before the presence and development of Aβ plaques and NTFs.…”