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Oxidative Mechanisms, Inflammation, and Alzheimer's Disease Pathogenesis

By M. Flint Beal, Cornell University, New York, NY, USA.

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There is a large body of evidence implicating oxidative damage in the pathogenesis of Alzheimer's disease. We previously identified increased concentration of 8-hydroxy-2-deoxyguanosine in both nuclear and mitochondrial DNA of Alzheimer's disease patients. We found a three-fold increase in the amount of oxidative damage to mitochondrial DNA as compared to age-matched controls. This may contribute to mitochondrial dysfunction since cytochrome oxidase activity was also decreased in postmortem brain tissue of Alzheimer's Disease subjects. It however is unclear how oxidative damage directly contributes to Alzheimer's disease pathogenesis. One possibility is that it may increase the production of β-amyloid as shown in vitro. It has been suggested that oxidative damage may increase the β-secretase cleavage of the amyloid precursor protein. We directly evaluated this possibility by crossing mice overexpressing the amyloid precursor protein with pathogenic mutations with mice deficient in manganese superoxide dismutase. The MnSOD deficient mice show no pathologic abnormalities but they show age-dependent increases in oxidative damage. We found that crossing the MnSOD deficient mice into the transgenic mouse model of Alzheimer's disease significantly accelerated β-amyloid deposition as well as β-amyloid concentrations isolated from the brain tissue of these mice. These findings provide a direct linkage between oxidative damage and increased β-amyloid deposition. It is therefore possible that treatment with antioxidants may help to slow the progression of Alzheimer's disease.

Citation: NeuroBiology of Aging, Volume 25, Number S2 , July 2004, Page 24

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