Human Molecular Genetics Advance Access published online on March 21, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl066
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1 Neurogenetics Laboratory, Neurological Sciences Institute, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006
* To whom correspondence should be addressed. Alzheimer's disease (AD) is a complex, neurodegenerative disease characterized by the impairment of cognitive function in elderly individuals. In a recent global gene expression study of APP transgenic mice, we found elevated expression of mitochondrial genes, which we hypothesize represents a compensatory response due to mitochondrial oxidative damage caused by the over-expression of mutant APP and/or amyloid beta (A
Received February 5, 2005
Revised March 14, 2006
Accepted March 14, 2006
Article
Mitochondria are a direct site of A
Maria Manczak 1,
Thimmappa S Anekonda 1,
Edward Henson 2,
Byung S Park 3,
Joseph Quinn 2,
and
P. Hemachandra Reddy 1 *
accumulation in Alzheimer's disease neurons: Implications for free radical generation and oxidative damage in disease progression
2 Department of Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97201
3 Division of Biostatistics, Department of Public Health and Preventive Medicine, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Rd, Portland, OR 97239
P. Hemachandra Reddy, E-mail: reddyh{at}ohsu.edu
Abstract 
). We investigated this hypothesis in a series of experiments examining what forms of APP and A localize to the mitochondria, and whether the presence of these species is associated with mitochondrial dysfunction and oxidative damage. Using immunoblotting, digitonin fractionation, immunofluorescence, and electron microscopy techniques, we found a relationship between mutant APP derivatives and mitochondria in brain slices from Tg2576 mice and in mouse neuroblastoma cells expressing mutant human APP. Further, to determine the functional relationship between mutant APP/A and oxidative damage, we quantified A levels, hydrogen peroxide production, cytochrome oxidase activity, and carbonyl proteins in Tg2576 mice and age-matched wild-type littermates. Hydrogen peroxide levels were found significantly increased in Tg2576 mice compared to age-matched wild-type littermates and directly correlated with levels of soluble A in Tg2576 mice, suggesting that soluble A may be responsible for the production of hydrogen peroxide in AD progression in Tg2576 mice. Cytochrome c oxidase activity was found decreased in Tg2576 mice compared to age-matched wild-type littermates, suggesting that mutant APP and soluble A impair mitochondrial metabolism in AD development and progression. An increase in hydrogen peroxide and a decrease in cytochrome oxidase activity were found in young Tg2576 mice, prior to the appearance of A plaques. These findings suggest that early mitochondrially targeted therapeutic interventions may be effective in delaying AD progression in elderly individuals and in treating AD patients.
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