This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The long-term goal of the proposed research is to develop a rational basis for neuroprotective strategies to delay or to prevent the onset of Alzheimer's disease (AD). Studies of mitochondrial function have shown mitochondrial abnormalities in postmortem brains in AD patients and imaging studies of brains from presymptomatic AD patients, suggesting that defects in cerebral energy metabolism may be a key factor in the development and progression of AD. Recent global gene expression studies have revealed an up-regulation of mitochondrial genes in 2-, 5- and 18-month-old mice from AD transgenic mouse line Tg2576, suggesting that mitochondria energy metabolism may be impaired by mutant amyloid precursor protein/Abeta (APP/A?) and that the up-regulation of mitochondrial gene expression may be a compensatory response to mutant APP/A? toxicity. In addition, biochemical studies have revealed increases in H2O2 production, oxidized DNA and proteins in Tg2576 mice compared to wild-type (wt) mice, also providing support that oxidative damage occurs in the AD mice. The proposed studies are pursuing the hypothesis that A? is a major factor in generating ROS and mitochondrial dysfunction. The following Specific Aims are investigating this hypothesis:
Aim 1. To determine whether mitochondrial dysfunction triggers mitochondrial gene expression in Tg2576 mice;
Aim 2. To determine whether mutant APP and/or A? leads to oxidative damage in Tg2576 mice;
and Aim 3. To determine whether mitochondrially targeted antioxidant catalase reduces ROS, mitochondrial toxicity and A? levels in Tg2576 mice and in an APP over-expressed cell-line model.
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