Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease
Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease
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DOI：
10.1073/pnas.0903563106
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发表时间：
2009-08-25
影响因子：
11.1
通讯作者：
Brinton, Roberta Diaz
中科院分区：
文献类型：
--
作者：
Yao, Jia;Irwin, Ronald W.;Brinton, Roberta Diaz
线粒体功能障碍已被认为在神经退行性疾病，包括阿尔茨海默病（AD）中发挥关键作用。为了解决线粒体功能障碍是否先于AD病理学的发展，我们在雌性三重转基因阿尔茨海默氏症小鼠（3xTg-AD）和年龄匹配的非转基因小鼠（nonTg）中进行了线粒体功能分析。早在3个月大时，3xTg-AD脑中的线粒体功能障碍通过线粒体呼吸降低和丙酮酸脱氢酶（PDH）蛋白水平和活性降低来证明。3xTg-AD小鼠还表现出增加的氧化应激，表现为增加的过氧化氢产生和脂质过氧化。3xTg-AD小鼠的线粒体淀粉样蛋白β（A β）水平在9个月时显著增加，并与A β与乙醇脱氢酶（ABAD）结合水平的增加在时间上相关。来自3xTg-AD小鼠海马的胚胎神经元表现出显著降低的线粒体呼吸和增加的糖酵解。这些分析的结果表明，受损的线粒体功能在胚胎海马神经元中是明显的，在整个生殖期的女性中持续不减，并在生殖衰老期间加剧。在非转基因对照小鼠中，氧化应激与生殖衰老一致，并伴随着线粒体功能的显着下降。3xTg-AD小鼠脑中的生殖衰老显著加剧了线粒体功能障碍。总的来说，数据表明在雌性AD小鼠模型中，在AD发病机制的早期发生显著的线粒体功能障碍。线粒体功能障碍为AD诊断前的脑代谢减退提供了合理的机制依据，并为预防AD提供了治疗靶点。
Mitochondrial dysfunction has been proposed to play a pivotal role in neurodegenerative diseases, including Alzheimer's disease (AD). To address whether mitochondrial dysfunction precedes the development of AD pathology, we conducted mitochondrial functional analyses in female triple transgenic Alzheimer's mice (3xTg-AD) and age-matched nontransgenic (nonTg). Mitochondrial dysfunction in the 3xTg-AD brain was evidenced by decreased mitochondrial respiration and decreased pyruvate dehydrogenase (PDH) protein level and activity as early as 3 months of age. 3xTg-AD mice also exhibited increased oxidative stress as manifested by increased hydrogen peroxide production and lipid peroxidation. Mitochondrial amyloid beta (A beta) level in the 3xTg-AD mice was significantly increased at 9 months and temporally correlated with increased level of A beta binding to alcohol dehydrogenase (ABAD). Embryonic neurons derived from 3xTg-AD mouse hippocampus exhibited significantly decreased mitochondrial respiration and increased glycolysis. Results of these analyses indicate that compromised mitochondrial function is evident in embryonic hippocampal neurons, continues unabated in females throughout the reproductive period, and is exacerbated during reproductive senescence. In nontransgenic control mice, oxidative stress was coincident with reproductive senescence and accompanied by a significant decline in mitochondrial function. Reproductive senescence in the 3xTg-AD mouse brain markedly exacerbated mitochondrial dysfunction. Collectively, the data indicate significant mitochondrial dysfunction occurs early in AD pathogenesis in a female AD mouse model. Mitochondrial dysfunction provides a plausible mechanistic rationale for the hypometabolism in brain that precedes AD diagnosis and suggests therapeutic targets for prevention of AD.