Mitochondria dysfunction of Alzheimer's disease cybrids enhances Aβ toxicity
Mitochondria dysfunction of Alzheimer's disease cybrids enhances Aβ toxicity
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DOI：
10.1111/j.1471-4159.2004.02438.x
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发表时间：
2004-06-01
影响因子：
4.7
通讯作者：
Oliveira, CR
中科院分区：
文献类型：
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作者：
Cardoso, SM;Santana, I;Oliveira, CR
阿尔茨海默病(AD)的大脑表现出高耗氧率和氧化应激，抗氧化防御改变，氧化多不饱和脂肪酸增加，过渡金属离子升高。阿尔茨海默病的线粒体功能障碍可能与这些观察结果有关，因为这可能通过形成活性氧物种(ROS)和释放启动程序性细胞死亡途径的分子来促进神经退行性细胞死亡。在这项研究中，我们分析了β-淀粉样肽(Abeta)对表达内源性线粒体DNA(MtDNA)的人畸胎癌(NT2)细胞、AD患者(AD囊体)和年龄匹配的对照组(对照囊体)的mtDNA的影响。除了发现AD细胞中细胞色素氧化酶活性降低、ROS升高和ATP水平降低外，当这些细胞系暴露于Abeta1-40时，我们观察到线粒体膜电位去极化增加，细胞质细胞色素c增加，caspase-3活性增加。当暴露于Abeta时，AD NT2胞体中与程序性细胞死亡相关的事件被激活的程度比在对照胞体或天然NT2细胞系中的激活程度更大，这表明线粒体衍生的线粒体功能障碍在AD退变中起到了作用。
Alzheimer's disease (AD) brain reveals high rates of oxygen consumption and oxidative stress, altered antioxidant defences, increased oxidized polyunsaturated fatty acids, and elevated transition metal ions. Mitochondrial dysfunction in AD is perhaps relevant to these observations, as such may contribute to neurodegenerative cell death through the formation of reactive oxygen species (ROS) and the release of molecules that initiate programmed cell death pathways. In this study, we analyzed the effects of beta-amyloid peptide (Abeta) on human teratocarcinoma (NT2) cells expressing endogenous mitochondrial DNA (mtDNA), mtDNA from AD subjects (AD cybrids), and mtDNA from age-matched control subjects (control cybrids). In addition to finding reduced cytochrome oxidase activity, elevated ROS, and reduced ATP levels in the AD cybrids, when these cell lines were exposed to Abeta 1-40 we observed excessive mitochondrial membrane potential depolarization, increased cytoplasmic cytochrome c, and elevated caspase-3 activity. When exposed to Abeta, events associated with programmed cell death are activated in AD NT2 cybrids to a greater extent than they are in control cybrids or the native NT2 cell line, suggesting a role for mtDNA-derived mitochondrial dysfunction in AD degeneration.