This is a proposal to study CNS structure and function in mice homozygous for a knock-in allele (PolgAmut/PolgAmut) encoding a proof-reading-deficient mitochondrial DNA polymerase. These mutant mice, denoted mtDNA mutator mice, accumulate elevated levels of somatic mtDNA mutations, which cause a progressive respiratory chain dysfunction and multiple signs of premature aging. Sequencing has established that somatic mtDNA levels are also elevated in the CNS of mtDNA mutator mice and preliminary data presented in this proposal show that these mutations cause wide-spread focal cytochrome c oxidase (COX) deficiency in the brain. Up to now, there have been no detailed studies of the brains of these animals. We propose characterizing central nervous system structures and function of mtDNA mutator and wildtype (wt) littermate mice at several different ages (3, 6 and 10 months). The wt mice will also be studied at 18 and 24 months of age. Once characterization of the CNS phenotype is completed, we propose to study the influence of treatment with antioxidant drugs as described in Project 1 and in collaboration with Dr. Bickford. In addition to CNS effects, we will also examine actions of these antioxidant drugs on the peripheral somatic changes in mt DNA mutator mice and wt controls. In subsequent studies, in collaboration with Project 3, we propose to study crosses of mt DNA mutator mice and wt controls with APP+PS1 mice. One aspect of Alzheimer's Disease (AD) that is not observed in current mouse models of AD is a loss of neurons. We predict that the combination of accumulation of mtDNA mutations observed in our mice with the mutant APP/PS1 expressed in the AD studied in Project 3 will result in neuronal loss. The hypothesis to be tested is that mitochondrial dysfunction predisposes to alzheimertype neuropathology and behavior disturbances. These experiments will test the hypothesis using genetic methods by determining if the mutator genotype causes aggravation and/or earlier onset of the APP+PS1 phenotype.
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