Beta-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase.
Beta-amyloid (betaA) peptide is strongly implicated in the neurodegeneration underlying Alzheimer's disease, but the mechanisms of neurotoxicity remain controversial. This study establishes a central role for oxidative stress by the activation of NADPH oxidase in astrocytes as the cause of betaA-induced neuronal death. betaA causes a loss of mitochondrial potential in astrocytes but not in neurons. The mitochondrial response consists of Ca2+-dependent transient depolarizations superimposed on a slow collapse of potential. The slow response is both prevented by antioxidants and, remarkably, reversed by provision of glutamate and other mitochondrial substrates to complexes I and II. These findings suggest that the depolarization reflects oxidative damage to metabolic pathways upstream of mitochondrial respiration. Inhibition of NADPH oxidase by diphenylene iodonium or 4-hydroxy-3-methoxy-acetophenone blocks betaA-induced reactive oxygen species generation, prevents the mitochondrial depolarization, prevents betaA-induced glutathione depletion in both neurons and astrocytes, and protects neurons from cell death, placing the astrocyte NADPH oxidase as a primary target of betaA-induced neurodegeneration.
Abramov
Andrey Y
AY
Mitochondrial Biology Group, Department of Physiology, University College London, London WC1E 6BT, United Kingdom.
Canevari
Laura
L
Duchen
Michael R
MR
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D002118:Calcium / Q000502:physiology; D016923:Cell Death; D002478:Cells, Cultured; D004789:Enzyme Activation; D005978:Glutathione / Q000378:metabolism; D007473:Ion Channels / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D019255:NADPH Oxidases / Q000378:metabolism* / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
D016229:Amyloid beta-Peptides; D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); D019255:NADPH Oxidases; D005978:Glutathione; D002118:Calcium