Shao Changxing, Xiong Shuling, Li Guo-Min, Gu Liya, Mao Guogen, Markesbery William R, Lovell Mark A
Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA.
Free Radic Biol Med. 2008 Sep 15;45(6):813-9. doi: 10.1016/j.freeradbiomed.2008.06.003. Epub 2008 Jun 11.
Eight-hydroxy-2'-deoxyguanosine (8-OHdG) is increased in the brain in late-stage Alzheimer's disease (LAD) and mild cognitive impairment (MCI). To determine if decreased base-excision repair contributes to these elevations, we measured oxoguanine glycosylase 1 (OGG1) protein and incision activities in nuclear and mitochondrial fractions from frontal (FL), temporal (TL), and parietal (PL) lobes from 8 MCI and 7 LAD patients, and 6 age-matched normal control (NC) subjects. OGG1 activity was significantly (P<0.05) decreased in nuclear specimens of FL, TL, and PL in MCI and LAD and in mitochondria from LAD FL and TL and MCI TL. Nuclear OGG1 protein was significantly decreased in LAD FL and MCI and LAD PL. No differences in mitochondrial OGG1 protein levels were found. Overall, our results suggest that decreased OGG1 activity occurs early in the progression of AD, possibly mediated by 4-hydroxynonenal inactivation and may contribute to elevated 8-OHdG in the brain in MCI and LAD.
在晚期阿尔茨海默病(LAD)和轻度认知障碍(MCI)患者的大脑中,8-羟基-2'-脱氧鸟苷(8-OHdG)水平升高。为了确定碱基切除修复功能降低是否导致了这些升高,我们检测了8例MCI患者、7例LAD患者以及6例年龄匹配的正常对照(NC)受试者额叶(FL)、颞叶(TL)和顶叶(PL)细胞核和线粒体组分中的氧鸟嘌呤糖基化酶1(OGG1)蛋白及切割活性。MCI和LAD患者FL、TL和PL的细胞核标本以及LAD患者FL和TL、MCI患者TL的线粒体中,OGG1活性显著降低(P<0.05)。LAD患者FL、MCI患者以及LAD患者PL的细胞核OGG1蛋白显著减少。线粒体OGG1蛋白水平未发现差异。总体而言,我们的结果表明,OGG1活性降低在AD进展早期就已出现,可能由4-羟基壬烯醛失活介导,并且可能导致MCI和LAD患者大脑中8-OHdG水平升高。