Fibrillar amyloid-β peptides kill human primary neurons via NADPH oxidase-mediated activation of neutral sphingomyelinase -: Implications for Alzheimer's disease
Fibrillar amyloid-β peptides kill human primary neurons via NADPH oxidase-mediated activation of neutral sphingomyelinase -: Implications for Alzheimer's disease
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DOI：
10.1074/jbc.m404635200
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发表时间：
2004-12-03
影响因子：
4.8
通讯作者：
Pahan, K
中科院分区：
文献类型：
--
作者：
Jana, A;Pahan, K
阿尔茨海默病是一种主要的痴呆疾病，其特征在于存在淀粉样蛋白斑块、神经元缠结和广泛的神经元凋亡。然而，阿尔茨海默病脑中神经元凋亡背后的机制知之甚少。本研究强调了中性鞘磷脂酶在原代神经元中纤维状Abeta肽诱导的细胞凋亡和细胞死亡中的重要性。A β 1 -42肽诱导神经元中鞘磷脂酶的激活和神经酰胺的产生。有趣的是，中性（N-SMase），而不是酸性（A-SMase），鞘磷脂酶参与A β 1 -42介导的神经元凋亡和细胞死亡。A β 1 -42诱导的神经酰胺的产生是氧化还原敏感的，因为活性氧参与了N-SMase的激活，而不是A-SMase。A β 1 -42肽诱导NADPH氧化酶介导的超氧自由基的产生，参与N-SMase的激活，但不是A-SMase，通过过氧化氢的神经元。此外，次黄嘌呤和黄嘌呤氧化酶产生的超氧自由基也通过过氧化氢酶敏感的途径诱导N-SMase的活化，而不是A-SMase。此外，反义敲低NADPH氧化酶的亚基p22 phox，抑制Abeta 1 -42诱导的神经元凋亡和细胞死亡。这些研究表明，纤维状A β 1 -42肽通过NADPH氧化酶-超氧化物-过氧化氢-NS-Mase-神经酰胺途径诱导神经元凋亡。
Alzheimer's disease is a major illness of dementia characterized by the presence of amyloid plaques, neurofibrillary tangles, and extensive neuronal apoptosis. However, the mechanism behind neuronal apoptosis in the Alzheimer's-diseased brain is poorly understood. This study underlines the importance of neutral sphingomyelinase in fibrillar Abeta peptide-induced apoptosis and cell death in human primary neurons. Abeta1-42 peptides induced the activation of sphingomyelinases and the production of ceramide in neurons. Interestingly, neutral (N-SMase), but not acidic (A-SMase), sphingomyelinase was involved in Abeta1-42-mediated neuronal apoptosis and cell death. Abeta1-42-induced production of ceramide was redox-sensitive, as reactive oxygen species were involved in the activation of N-SMase but not A-SMase. Abeta1-42 peptides induced the NADPH oxidase-mediated production of superoxide radicals in neurons that was involved in the activation of N-SMase, but not A-SMase, via hydrogen peroxide. Consistently, superoxide radicals generated by hypoxanthine and xanthine oxidase also induced the activation of N-SMase, but not A-SMase, through a catalase-sensitive pathway. Furthermore, antisense knockdown of p22phox, a subunit of NADPH oxidase, inhibited Abeta1-42-induced neuronal apoptosis and cell death. These studies suggest that fibrillar Abeta1-42 peptides induce neuronal apoptosis through the NADPH oxidase-superoxide-hydrogen peroxide-NS-Mase-ceramide pathway.