MITOCHONDRIAL, TAU, AND AGING

缺乏线粒体超氧化物歧化酶(SOD2)的小鼠表现出线粒体受损！中的函数 新生儿死亡与心肌病、贫血、肝脏高脂血症、细胞增强的关系 死亡和基因组不稳定，以及活性氧物种的过量产生。可能是最引人注目的 这些小鼠体内发育的表型集中在大脑中。超过两周龄的Sod2基因缺失小鼠 迅速发展为地区性海绵状脑病，伴有胶质细胞增多症 神经退行性变与脑病本身不是共定位的。我们已经描述了许多 Sod2基因缺失小鼠的表型与有效的抗氧化剂干预相结合，以防止或 减轻线粒体氧化应激的病理后果。 这一提议将检验一种假说，即随着时间的推移，线粒体氧化应激增加与 伴有突触功能障碍和tau蛋白过度磷酸化。我们建议采取干预措施减少 线粒体氧化应激也会减少突触功能障碍和tau病理。我们还提议 线粒体氧化应激显著影响成年小鼠的大脑功能，并将通过 时间和组织特异性可诱导的Sod2基因敲除的特征。我们建议对这些进行测试 通过以下具体目标进行假设： 1.Sod2基因缺失小鼠突触体功能的增龄特征。这 特定的目标将检验这一假设，即在10至20天龄期间，来自Sod2的突触体 无合子小鼠的ROS增加，直接影响线粒体功能。 2.通过对Sod2基因缺失小鼠tau蛋白过度磷酸化的研究 定量免疫印迹和基因表达谱分析。我们已经把这部小说写成了 观察到tau过度磷酸化是线粒体氧化应激的结果。这 特定的目的将表征Sod2基因缺失小鼠tau蛋白过度磷酸化的发展 通过对tau的蛋白质组学研究，结合基因表达谱。 3.神经元特异性可诱导的Sod2基因敲除的特征。在描述了 线粒体氧化应激在突触体和tau中的后果，我们将研究 线粒体功能障碍在成年小鼠脑中的后果。具体来说，我们将a)评估 可诱导的Sod2基因缺失小鼠一生中不同时间的神经病理学 年龄对不同时间触发的线粒体氧化应激病理结果的影响 一生中的次数，以及b)评估tau的磷酸化状态，使用年龄作为 自变量。

Mice lacking mitochondrial superoxide dismutase (SOD2) show compromised mitochondria! function in association with neonatal lethality and cardiomyopathy, anemia, hyperlipidemia in the liver, enhanced cell death and genomic instability, and excess production of reactive oxygen species. Perhaps the most striking phenotypes that develop in these mice are centered in the brain. Sod2 null mice over two weeks of age rapidly develop a regionally specific spongiform encephalopathy, accompanied by gliosis in addition to a neurodegeneration not colocalized with the encephalopathy itself. We have characterized many of the phenotypes in sod2 null mice in conjunction with effective antioxidant interventions that prevent or attenuate the pathological consequences of mitochondrial oxidative stress. This proposal will test the hypothesis that increasing mitochondrial oxidative stress over time is associated with synaptic dysfunction and hyperphosphorylation of tau. We propose that interventions that reduce mitochondrial oxidative stress will also reduce synaptic dysfunction and tau pathology. We also propose that mitochondrial oxidative stress significantly impacts brain function in adult mice, and will test this via characterization of an temporal and tissue specific inducible knockout of sod2. We propose to test these hypotheses via the following specific aims: 1. Characterization of synaptosomal function with increasing age in sod2 nullizygous mice. This specific aim will test the hypothesis that between 10and 20 days of age, synaptosomes from sod2 nullizygous mice have increased ROSthat directly impacts mitochondrial function. 2. Characterize the development of hyperphosphorylation of tau in sod2 nullizygous mice though quantitative Western blotting and gene expression profiling. We have made the novel observation that tau is hyperphosphorylated as a result of mitochondrial oxidative stress. This specific aim will characterize the development of hyperphosphorylation in tau in sod2 null mice through proteomic studies on tau, in conjunction with gene expression profiling. 3. Characterization of a neuronal specific inducible knockout of sod2. Having characterized the consequences of mitochondrial oxidative stress in synaptosomes and tau, we will study the consequences of mitochondrial dysfunction in adult mouse brain. Specifically we will a) evaluate neuropathology of inducible sod2 null mice at various times throughout their lives to evaluate the effect of age on pathological outcomes from mitochondrial oxidative stress triggered at different times throughout life, and b) evaluate the phosphorylation status of tau, using age as an independent variable.