Processing Of Oxidative Stress In Alzheimer

Aging

Investigators

Linked publications, trials & patents

Abstract

Summary of work: Several cellular markers of oxidative stress are higher in cells from Alzheimer disease (AD) patients as compared to normal age-matched controls. These markers include oxidative damage to lipids, proteins and DNA in various tissues from AD subjects. It has been proposed that AD cells may have a defect in the DNA repair processing of oxidative base lesion leading to accumulation of DNA damage. Using DNA substrates containing both pyrimidine and purine lesions we have investigated the repair of oxidative base lesions in whole cell extracts from cultured AD lymphoblasts. Our data indicate that oxidative DNA lesions are repaired efficiently in AD lymphoblasts compared to controls. In normal cells, oxidative DNA damage is mainly repaired by the base excision repair (BER) pathway. We are investigating the hypothesis that DNA repair is altered in AD by measuring BER capacity in whole cell and mitochondrial extracts obtained from well established animal models for AD, since the mitochondrial DNA seems to be preferentially target for oxidative damage. We have used three mouse model systems for AD, transgenic mice expressing mutant amyloid precursor protein 1 (APP1) gene; a double transgenic mouse expressing mutant APP1 plus mutant presenilin 1; and a triple transgenic mouse expressing the two previous genes plus a mutated form of tau, which is involved in the formation of plaques and tangles in the AD brain. Since these mice develop AD-like symptoms in an age-associated fashion, we compare DNA repair activities in young and old mice, i.e. before and after the onset of the disease. Recent reports have shown that corpus callosum and hippocampus atrophy are hallmarks of AD brains, suggesting that some regions are more susceptible to AD-induced degeneration. Thus, we are measuring repair capacity in extracts of different brain regions in normal and AD-model mice. We also follow age-associated changes in DNA repair capacity in these regions. Our results show that BER activities in mitochondria varied greatly among 5 brain regions, striatum, frontal cortex, cerebellum, hippocampus and brain steam, with brain steam having highest and striatum the lowest DNA glycosylase activities. We observed a general decrease in BER efficiency in brain with age; however the age-associated changes also differ among the regions. In contrast, we observed an increase in BER activity in some brain regions of the older AD-model mice when compared with young, pre-symptomatic mice. We are now directly testing the hypothesis that 8-oxoG accumulation plays a role in neurodegenerative processes. For that, mice deficient in the oxoguanine DNA glycosylase (OGG1) are injected with model drugs for neurodegenerative diseases, such as kainic acid, or subjected to ischemia-reperfusion models. These animals completely lack 8-oxoG removal in mitochondria and show decrease activity in the nuclei. We find that OGG1-/- mice develop a larger infarct area after ischemia-reperfusion and this correlates with higher degree of motor dysfunction. These results indicate that 8-oxoG accumulation may play a direct role in the development of neurodegenerative diseases.