The role of an astrocytic NADPH oxidase in the neurotoxicity of amyloid beta peptides
The role of an astrocytic NADPH oxidase in the neurotoxicity of amyloid beta peptides
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DOI：
10.1098/rstb.2005.1766
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发表时间：
2005-12-29
影响因子：
6.3
通讯作者：
Duchen, MR
中科院分区：
文献类型：
--
作者：
Abramov, AY;Duchen, MR
淀粉样β肽（A β）在阿尔茨海默病的CNS中积累。完整肽（1-42）或25-35片段对培养的神经元都有毒性。我们已经使用荧光成像技术，以探讨从大鼠或小鼠皮层或海马制备的星形胶质细胞/神经元混合培养物中的神经毒性机制，并发现A β优先作用于星形胶质细胞，但导致神经元死亡。A β导致星形胶质细胞中[Ca 2 +]（c）的偶发性瞬时增加，与活性氧（ROS）和谷胱甘肽耗竭的钙依赖性增加有关。这导致线粒体电位缓慢消散，其上叠加了突然的钙依赖性瞬时去极化。线粒体。线粒体底物谷氨酸盐、丙酮酸盐或琥珀酸甲酯以及NADPH氧化酶（NOX）抑制剂可逆转去极化，表明其反映了线粒体复合物I上游代谢途径的氧化损伤。AD诱导的ROS增加和线粒体去极化在从缺乏NOX组分gp 91（phox）的转基因小鼠培养的细胞中不存在。NOX抑制剂和gp 91（phox）基因敲除小鼠中，A β暴露24小时后的神经元死亡显著减少。因此，通过提高星形胶质细胞中的[Ca 2 +]（c），AD激活NOX，产生传递到神经元的氧化应激，导致神经元死亡。
Amyloid beta peptide (A beta) accumulates in the CNS in Alzheimer's disease. Both the full peptide (1-42) or the 25-35 fragment are toxic to neurons in culture. We have used fluorescence imaging technology to explore the mechanism of neurotoxicity in mixed asytrocyte/neuronal cultures prepared from rat or mouse cortex or hippocampus, and have found that A beta acts preferentially on astrocytes but causes neuronal death. A beta causes sporadic transient increases in [Ca2+](c) in astrocytes, associated with a calcium dependent increased generation of reactive oxygen species (ROS) and glutathione depletion. This caused a slow dissipation of mitochondrial potential on which abrupt calcium dependent transient depolarizations were superimposed. The mitochondrial. depolarization was reversed by mitochondrial substrates glutamate, pyruvate or methyl succinate, and by NADPH oxidase (NOX) inhibitors, suggesting that it reflects oxidative damage to metabolic pathways upstream of mitochondrial complex I. The AD induced increase in ROS and the mitochondrial depolarization were absent in cells cultured from transgenic mice lacking the NOX component, gp91(phox). Neuronal death after 24 h of A beta exposure was dramatically reduced both by NOX inhibitors and in gp91(phox) knockout mice. Thus, by raising [Ca2+](c) in astrocytes, AD activates NOX, generating oxidative stress that is transmitted to neurons, causing neuronal death.