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Human Molecular Genetics Advance Access originally published online on March 21, 2006
Human Molecular Genetics 2006 15(9):1437-1449; doi:10.1093/hmg/ddl066
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Mitochondria are a direct site of Aß accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression

Maria Manczak1, Thimmappa S. Anekonda1, Edward Henson2, Byung S. Park3, Joseph Quinn2 and P. Hemachandra Reddy1,*

1Neurogenetics Laboratory, Neurological Sciences Institute, Oregon Health and Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA, 2Department of Neurology and 3Division of Biostatistics, Department of Public Health and Preventive Medicine, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR 97201, USA

* To whom correspondence should be addressed. Tel: +1 5034182625; Fax: +1 5034182501; Email: reddyh{at}ohsu.edu

Received February 5, 2006; Accepted March 14, 2006

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 because of mitochondrial oxidative damage caused by the over-expression of mutant APP and/or amyloid beta (Aß). We investigated this hypothesis in a series of experiments examining what forms of APP and Aß 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/Aß and oxidative damage, we quantified Aß levels, hydrogen peroxide production, cytochrome oxidase activity and carbonyl proteins in Tg2576 mice and age-matched wild-type (WT) littermates. Hydrogen peroxide levels were found to be significantly increased in Tg2576 mice when compared with age-matched WT littermates and directly correlated with levels of soluble Aß in Tg2576 mice, suggesting that soluble Aß may be responsible for the production of hydrogen peroxide in AD progression in Tg2576 mice. Cytochrome c oxidase activity was found to be decreased in Tg2576 mice when compared with age-matched WT littermates, suggesting that mutant APP and soluble Aß 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 Aß 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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