RT Journal Article
SR Electronic
T1 β-Amyloid Peptides Induce Mitochondrial Dysfunction and Oxidative Stress in Astrocytes and Death of Neurons through Activation of NADPH Oxidase
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 565
OP 575
DO 10.1523/JNEUROSCI.4042-03.2004
VO 24
IS 2
A1 Abramov, Andrey Y.
A1 Canevari, Laura
A1 Duchen, Michael R.
YR 2004
UL http://www.jneurosci.org/content/24/2/565.abstract
AB 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.