title: Is Alzheimer's disease a disorder of mitochondria-associated membranes?
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 gamma-secretase activity. We hypothesize that presenilins play a role in maintaining MAM function, and that not only altered amyloid-beta 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 gamma-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.
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY, USA. eas3@columbia.edu
authors.forename: Eric A
authors.initials: EA
authors.lastname: Schon
authors.forename: Estela
authors.initials: E
authors.lastname: Area-Gomez
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D006801:Humans; D050356:Lipid Metabolism; D028361:Mitochondrial Diseases / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051336:Mitochondrial Membranes / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D008954:Models, Biological; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D053766:Presenilin-2 / Q000235:genetics / Q000378:metabolism
chemical_list: C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D053829:Amyloid Precursor Protein Secretases