There is increasing evidence that both mitochondrial dysfunction and oxidative damage contributes to Alzheimer's Disease (AD) pathogenesis. In our previous grant period, we found an increase in cytochrome oxidase mtDNA mutations in both aging and AD, and an increase in mtDNA mutations in the control region of mtDNA. There may be a direct interaction of amyloid-p peptide (A?) with Cu2+ to induce cytochrome oxidase dysfunction, and with the A? alcohol dehydrogenase within mitochondria to increase free radical generation. We propose to isolate mitochondria from both a double APR mutant and a triple transgenic mouse model of AD, to measure mitochondrial A? levels and to correlate levels with mitochondrial bioenergetics, free radical production, calcium uptake capacity and ability to activate the mitochondrial permeability transition. We will also determine APR cleavage and A? production in cultured neurons under conditions of increased or decreased mitochondrial dysfunction and oxidative stress. A partial deficiency of manganese superoxide dismutase (MnSOD), increases oxidative damage and exacerbates A? deposition in a transgenic mouse model of AD. We propose to cross a transgenic mouse model of AD with mice overexpressing MnSOD to determine whether this will ameliorate oxidative damage, A|3 deposition and spatial memory deficits. Lastly, we found that both coenzyme Q10 and genetic deficiency of NOS2 reduce A? deposition and improve survival of a transgenic mouse model of AD. We, therefore, propose to determine whether optimal administration of coenzyme Q10 and of a selective NOS 2 inhibitor can improve oxidative damage, A? deposition and spatial memory deficits in transgenic mouse models of AD. These studies will further define the role of mitochondrial dysfunction and oxidative damage in AD pathogenesis and have the potential of leading to important new therapies.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Cell Death in Neurodegeneration Study Section (CDIN)
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Refolo, Lorenzo
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Weill Medical College of Cornell University
Schools of Medicine
New York
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