MITOCHONDRIAL, TAU, AND AGING

缺乏线粒体超氧化物歧化酶（SOD2）的小鼠显示线粒体受损！函数

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.