Altered 8-oxoguanine glycosylase in mild cognitive impairment and late-stage Alzheimer's disease brain

Abstract

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.

Levels of reduced and oxidized coenzyme Q-10 and 8-hydroxy-2′-deoxyguanosine in the CSF of patients with Alzheimer’s disease demonstrate that mitochondrial oxidative damage and/or oxidative DNA damage contributes to the neurodegenerative process

“…Recently, Shao et al [16] showed that intranuclear 8-OHdG levels from frontal, temporal, and parietal lobes were elevated in AD patients comparison to healthy controls. The plasma and urine levels of 8-OHdG in AD patients are significantly higher than those of controls [31].…”

“…In these studies, immunochemical examination demonstrated that brain tissues from AD patients have between 1.2 and 3.1 times higher levels of intranuclear 8-hydroxy-2 0 -deoxyguanosine (8-OHdG) than control tissue [14][15][16]. Superoxide dismutase catalyzes the conversion of reactive oxygen to oxygen and hydrogen peroxide; the latter is decomposed to oxygen and water by the enzymes catalase and glutathione peroxidase.…”

Oxidative DNA damage in disease—Insights gained from base excision repair glycosylase‐deficient mouse models

“…Decreased OGG1 activity and increased 8-oxoG content in the brain were found to be correlated with development of Alzheimer's disease and cognitive impairment [Iida et al, 2002;Wang et al, 2005;Mao et al, 2007;Shao et al, 2008;Dorszewska et al, 2009]. Interestingly, while one of these studies reported a specific increase in the mitochondrial OGG1-2a isoform in brains exhibiting the pathological state [Iida et al, 2002], another study did not observe an increase in the mitochondrial OGG1 protein content [Shao et al, 2008]. Despite these reported correlations between OGG1 and Alzheimer's disease in human cohorts, there is a lack of studies on Alzheimer's susceptibility using any of the multiple OGG1-deficient or overexpressing mouse models.…”

Analyzing Nootropic Effect of &lt;i&gt;Phyllanthus reticulatus&lt;/i&gt; Poir. on Cognitive Functions, Brain Antioxidant Enzymes and Acetylcholinesterase Activity against Aluminium-Induced Alzheimer’s Model in Rats: Applicable for Controlling the Risk Factors of Alzheimer’s Disease

“…Numerous studies exhibit an increase in oxidative DNA damage in the brain's of subjects with AD [25]. The greatest marked DNA adduct defined is 8-hydroxy-2-deoxyguanosine (8-OHdG) [26]. On the other hand advanced glycation end products are produced due to posttranslational modifications of proteins and may play a role in AD that is connected to oxidative modifications of Aβ peptides and tau [27].…”