β-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase
β-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase
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DOI：
10.1523/jneurosci.4042-03.2004
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发表时间：
2004-01-14
影响因子：
5.3
通讯作者：
Duchen, MR
中科院分区：
文献类型：
--
作者：
Abramov, AY;Canevari, L;Duchen, MR
β-淀粉样蛋白(β-A)与阿尔茨海默病的神经退行性变密切相关，但神经毒性的机制仍存在争议。这项研究通过激活星形胶质细胞中的NADPH氧化酶作为βA诱导的神经元死亡的原因，确立了氧化应激的核心作用。βA导致星形胶质细胞线粒体电位的丧失，但不会导致神经元线粒体电位的丧失。线粒体的反应由钙离子依赖的瞬间去极化叠加在缓慢的电位崩溃上组成。这种缓慢的反应既被抗氧化剂阻止，又被谷氨酸和其他线粒体底物提供给复合体I和II而显著逆转。这些发现表明，去极化反映了线粒体呼吸上游代谢途径的氧化损伤。二苯碘或4-羟基-3-甲氧基苯乙酮抑制NADPH氧化酶可阻断βA诱导的活性氧生成，阻止线粒体去极化，阻止βA诱导的神经元和星形胶质细胞谷胱甘肽耗竭，保护神经元免受细胞死亡，使星形胶质细胞NADPH氧化酶成为βA诱导的神经变性的主要靶点。
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.