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The Journal of Neuroscience, January 14, 2004, 24(2):565-575; doi:10.1523/JNEUROSCI.4042-03.2004

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Neurobiology of Disease
-Amyloid Peptides Induce Mitochondrial Dysfunction and Oxidative Stress in Astrocytes and Death of Neurons through Activation of NADPH Oxidase

Andrey Y. Abramov,¹ Laura Canevari,² and Michael R. Duchen¹

¹Mitochondrial Biology Group, Department of Physiology, University College London, London WC1E 6BT, United Kingdom, and ²Division of Neurochemistry, Institute of Neurology, London WC1N 3BG, United Kingdom

-Amyloid (A) 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 A-induced neuronal death. A 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 A-induced reactive oxygen species generation, prevents the mitochondrial depolarization, prevents A-induced glutathione depletion in both neurons and astrocytes, and protects neurons from cell death, placing the astrocyte NADPH oxidase as a primary target of A-induced neurodegeneration.

Key words: Alzheimer; astrocyte; astroglia; calcium; mitochondria; NADPH; neuron

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Received Sep 2, 2003; revised November 13, 2003; accepted November 14, 2003.

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