Is Alzheimer's Disease a Disorder of Mitochondria-Associated Membranes?

Abstract

Abstract. The subcellular localization of presenilin-1 (PS1) and presenilin-2 (PS2), two proteins that, when mutated, cause familial Alzheimer's disease (AD), is controversial. We have discovered that mitochondria-associated membranes (MAM) -a specialized subcompartment of the endoplasmic reticulum (ER) involved in lipid metabolism and calcium homeostasis that physically connects ER to mitochondria -is the predominant subcellular location for PS1 and PS2, and for γ-secretase activity. We hypothesize that presenilins play a role in maintaining MAM function, and that not only altered amyloid-β levels and hyperphosphorylated tau, but also many other features of AD (e.g., altered phospholipid and cholesterol metabolism, aberrant calcium homeostasis, and abnormal mitochondrial dynamics) result from compromised MAM function. The localization of presenilins and γ-secretase in MAM may help reconcile disparate ideas regarding the pathogenesis of AD, under a unifying hypothesis that could explain many features of both sporadic and familial AD, thereby taking AD research in a new and fruitful direction.Keywords: Alzheimer's disease, calcium, cholesterol, endoplasmic reticulum (ER), mitochondria, mitochondria-associated membranes (MAM), phospholipids ALZHEIMER'S DISEASEAlzheimer's disease (AD), the most common late onset neurodegenerative dementing disorder, is characterized by progressive neuronal loss, especially in the hippocampus and cortex [1]. The two main histopathological hallmarks of AD are the accumulation of extracellular neuritic plaques, containing amyloid-β (Aβ), and of neurofibrillary tangles, consisting mainly of hyperphosphorylated forms of the microtubule-associated protein tau [1]. Most AD patients are sporadic (SAD), but three genes have been associated with the familial form (FAD): amyloid-β protein precursor (AβPP), presenilin-1 (PS1), and presenilin-2 (PS2). Clinically, FAD is similar to SAD but has earlier onset. Presenilins are components of the γ-secretase complex (also containing APH1, nicastrin, and PEN2) that, together with β-secretase, processes AβPP to produce Aβ [1]. In the mainstream view, both SAD and FAD arise when AβPP is processed to Aβ, which accumulates in extracellular plaques. Aβ is toxic to cells and the resulting stress promotes tau hyperphosphorylation, leading to the tangles. The overall process has been called the "amyloid cascade" hypothesis [2,3]. This hypothesis reconciles findings from different approaches to the disease and has served as the basis for many key experiments in vivo and in vitro. However, certain questions that are central to understanding the pathogenesis of AD and the processing of Aβ remain unsolved.The first question concerns features of AD that are not obviously linked to plaque or tangle formation. While plaques and tangles are hallmarks of the disease, other apparently unrelated laboratory abnormali-

ApoE4 upregulates the activity of mitochondria‐associated ER membranes

“…Both lines of evidence support the view that PS1 and PS2, in addition to generating Aβ, are negative regulators of MAM function 7 and that these alterations play a critical role in the pathogenesis of the disease (the “MAM hypothesis”) 11, 12. If the hypothesis has any validity, it should accommodate ApoE4's role as a risk factor in the disease, that is, ApoE4 should play a role in mediating MAM behavior, either directly or indirectly.…”

A mitochondrial bioenergetic etiology of disease

“…Excessive mitochondrial Ca 2+ exposure can also increase mitochondrial ROS production and activate the mtPTP. Mitochondrially destined Ca 2+ is released from the endoplasmic reticulum within the mitochondria-associated membranes (MAMs), and MAMs harbor the presenilin complexes (61,62). Inappropriate MAM Ca 2+ regulation can cause chronic mitochondrial stress by increasing mitochondrial ROS production and Ca 2+ activation of the mtPTP.…”

A Fungal Sarcolemmal Membrane-Associated Protein (SLMAP) Homolog Plays a Fundamental Role in Development and Localizes to the Nuclear Envelope, Endoplasmic Reticulum, and Mitochondria

“…ERMES, a homolog of which has not yet been identified in higher eukaryotes, was suggested to be involved in phospholipid exchange, calcium signaling, and mitochondrial physiology (70)(71)(72). Recently, ER-mitochondrion contact sites have been shown to play a role in neurodegenerative diseases like Alzheimer's disease and amyotrophic lateral sclerosis (73,74).…”