β-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase

AY Abramov, L Canevari, MR Duchen - Journal of Neuroscience, 2004 - Soc Neuroscience
AY Abramov, L Canevari, MR Duchen
Journal of Neuroscience, 2004Soc Neuroscience
β-Amyloid (βA) 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 βA-induced neuronal death. βA 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 …
β-Amyloid (βA) 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 βA-induced neuronal death. βA 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 βA-induced reactive oxygen species generation, prevents the mitochondrial depolarization, prevents βA-induced glutathione depletion in both neurons and astrocytes, and protects neurons from cell death, placing the astrocyte NADPH oxidase as a primary target of βA-induced neurodegeneration.
Soc Neuroscience