title: Mitochondrial Abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease.
abstract: Although amyloid-beta peptide (Abeta) is the neurotoxic species implicated in the pathogenesis of Alzheimer's disease (AD), mechanisms through which intracellular Abeta impairs cellular properties, resulting in neuronal dysfunction, remain to be clarified. Here we demonstrate that intracellular Abeta is present in mitochondria from brains of transgenic mice with targeted neuronal overexpression of mutant human amyloid precursor protein and AD patients. Abeta progressively accumulates in mitochondria and is associated with diminished enzymatic activity of respiratory chain complexes (III and IV) and a reduction in the rate of oxygen consumption. Importantly, mitochondria-associated Abeta, principally Abeta42, was detected as early as 4 months, before extensive extracellular Abeta deposits. Our studies delineate a new means through which Abeta potentially impairs neuronal energetics, contributing to cellular dysfunction in AD.
authors.affiliation: Department of Surgery, College of Physicians & Surgeons of Columbia University, New York, New York 10032, USA.
authors.forename: Casper
authors.initials: C
authors.lastname: Caspersen
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Yao
authors.forename: Alexander
authors.initials: A
authors.lastname: Sosunov
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Joyce W
authors.initials: JW
authors.lastname: Lustbader
authors.forename: Hong Wei
authors.initials: HW
authors.lastname: Xu
authors.forename: David
authors.initials: D
authors.lastname: Stern
authors.forename: Guy
authors.initials: G
authors.lastname: McKhann
authors.forename: Shi Du
authors.initials: SD
authors.lastname: Yan
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics; D000818:Animals; D001921:Brain / Q000648:ultrastructure; D020126:Brefeldin A / Q000494:pharmacology; D002540:Cerebral Cortex / Q000473:pathology; D003600:Cytosol / Q000378:metabolism; D045222:Electron Transport Chain Complex Proteins / Q000737:chemistry; D004734:Energy Metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D016253:Microscopy, Immunoelectron; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D008954:Models, Biological; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D018384:Oxidative Stress; D010101:Oxygen Consumption; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics*; D010447:Peptide Hydrolases / Q000378:metabolism; D058225:Plaque, Amyloid / Q000473:pathology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D045222:Electron Transport Chain Complex Proteins; D010446:Peptide Fragments; D011500:Protein Synthesis Inhibitors; C075222:amyloid beta-protein (1-42); D020126:Brefeldin A; D010447:Peptide Hydrolases