Mitochondrial Abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease.
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.
Caspersen
Casper
C
Department of Surgery, College of Physicians & Surgeons of Columbia University, New York, New York 10032, USA.
Wang
Ning
N
Yao
Jun
J
Sosunov
Alexander
A
Chen
Xi
X
Lustbader
Joyce W
JW
Xu
Hong Wei
HW
Stern
David
D
McKhann
Guy
G
Yan
Shi Du
SD
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
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