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). Recently, several lines of evidence have revealed that age-related reactive oxygen species (ROS) is associated with mitochondrial oxidative damage in late-onset neurodegenerative diseases such as 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, preliminary biochemical studies have revealed increases in hydrogen peroxide, oxidized DNA and proteins in Tg2576 mice compared to wild-type mice, also providing support that oxidative damage occurs in the AD mice. These studies have also revealed that 4kDa A? is associated with mitochondria and is responsible for generating ROS and mitochondrial dysfunction. Further, the studies of Tg2576 mice have found that soluble A? significantly correlates with hydrogen peroxide in 2-month-old Tg2576 mice. Taken together, all these results suggest that mutant APP and/or A? generates free radicals and mitochondrial dysfunction early in disease progression and that the up-regulation of mitochondrial genes may be a compensatory response to mitochondrial toxicity. The proposed studies will pursue the hypothesis that A? is a major factor in generating ROS and mitochondrial dysfunction. The following Aims are proposed to investigate 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.
Aims 1 and 2 will investigate how mutant APP and/or A? relate to mitochondrial dysfunction throughout the lifespan of Tg2576 mice.
Aim 3 will provide a mechanistic test of the hypothesis by characterizing neuroprotective mechanisms of mitochondrial oxidative damage, and will take us closer to identifying novel therapies of AD.
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