Decreased base excision repair and increased helicase activity in Alzheimer's disease brain.
Recent studies show an increase in DNA oxidation in brain and cerebrospinal fluid (CSF), and decreased levels of the free repair product in CSF in Alzheimer's disease (AD). This is a study of the activity of the base excision repair enzyme, 8-oxoguanine glycosylase (responsible for the excision of 8-oxoguanine), and DNA helicase activity in nuclear protein samples from four brain regions of 10 AD and eight age-matched control subjects. Statistically significant (p<0.05) decreases in 8-oxoguanine glycosylase activity were observed in the nuclear fraction of AD hippocampal and parahippocampal gyri (HPG), superior and middle temporal gyri (SMTG), and inferior parietal lobule (IPL). DNA helicase activity was elevated in all nuclear samples except the IPL with statistically significant elevations in the HPG and CER. Statistically significant depletion of helicase activity was observed in the nuclear fraction in AD IPL. Our results demonstrate that the repair capabilities for 8-oxoguanine are decreased in AD. The modest increase in DNA helicase activity in some brain regions in AD may interfere with base excision repair mechanisms. Overall, the decreased repair of DNA damage could be involved in the pathogenesis of neurodegeneration in AD.
Lovell
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Sanders-Brown Center on Aging and Alzheimer's Disease Research Center, 101 Sanders-Brown Building, University of Kentucky, 800 South Limestone Street, Lexington, KY 40536-0230, USA. malove2@pop.uky.edu
Xie
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Markesbery
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D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000201:enzymology*; D002458:Cell Fractionation; D002467:Cell Nucleus / Q000201:enzymology; D004247:DNA / Q000378:metabolism; D004265:DNA Helicases / Q000032:analysis / Q000378:metabolism*; D004260:DNA Repair; D043382:DNA-Formamidopyrimidine Glycosylase; D005260:Female; D006801:Humans; D008297:Male; D009699:N-Glycosyl Hydrolases / Q000032:analysis / Q000378:metabolism; D010084:Oxidation-Reduction
D004247:DNA; D009699:N-Glycosyl Hydrolases; D043382:DNA-Formamidopyrimidine Glycosylase; D004265:DNA Helicases