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. 2008 Sep 15;45(6):813-9.
doi: 10.1016/j.freeradbiomed.2008.06.003. Epub 2008 Jun 11.

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

Changxing Shao  1 , Shuling Xiong, Guo-Min Li, Liya Gu, Guogen Mao, William R Markesbery, Mark A Lovell
Affiliations

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

Changxing Shao et al. Free Radic Biol Med. .

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.

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Figures

Fig. 1
Fig. 1
Western blot analysis of representative nuclear (lanes 1–3) and mitochondrial (lanes 4–6) fractions probed for lamin A, a nuclear marker, and porin, a mitochondrial marker. There was no cross-contamination between fractions.
Fig. 2
Fig. 2
Representative image showing OGG1 incision activity of nuclear specimens from normal control (NC; lanes 1–5) and MCI (lanes 6–11) subjects. OGG1 activity was indicated by incision of the duplex oligonucleotide (top band) to form a smaller fragment (lower band). Lane 12 shows that there was no activity in a representative protein specimen heated at 100°C before initiation of the assay (blank).
Fig. 3
Fig. 3
(A) OGG1-mediated incision activities of nuclear specimens from NC, MCI, and LAD subjects expressed as mean±SEM % activity in the incised band relative to the total radioactivity in the lane. OGG1 activity in frontal lobe (FL), parietal lobe (PL), and temporal lobe (TL) of MCI and LAD subjects was significantly decreased (P<0.05) compared to NC subjects. (B) OGG1-mediated incision of the radiolabeled oligonucleotide by mitochondrial specimens from NC, MCI, and LAD subjects (mean±SEM % total radioactivity/lane). BER activity in frontal lobe (FL) of LAD subjects and temporal lobe (TL) from MCI and LAD subjects was significantly decreased (P<0.05) compared to NC subjects.
Fig. 4
Fig. 4
(A) Representative Western blots of nuclear specimens from NC (4A—1; lanes 1–5) and MCI (4A—1; lanes 6–11) and NC (4A—2; lanes 1–5) and LAD (4A—2; lanes 6–10) subjects probed for OGG1 and lamin A (nuclear loading control). (B) Representative Western blots of mitochondrial specimens from NC (4B—1; lanes 1–5) and MCI (4B—1; lanes 6–11) and NC (4B—2; lanes 1–5) and LAD (4B—2; lanes 6–11) subjects probed for OGG1 and porin (mitochondrial loading control).
Fig. 5
Fig. 5
(A) Nuclear OGG1 protein levels (mean±SEM % control) in MCI, LAD, and NC subjects. OGG1 was significantly decreased in frontal lobe (FL) of LAD subjects. In contrast, OGG1 was significantly increased in MCI temporal lobe (TL) and CER. (B) Mitochondrial OGG1 protein levels (mean±SEM % control) in MCI, LAD, and NC subjects. Mitochondrial OGG1 protein was not significantly different in any of the subjects or brain regions studied.
Fig. 6
Fig. 6
Representative mitochondrial specimens from 3 NC (lanes 1–3), 3 MCI (lanes 4–6), and 3 LAD (lanes 7–9) subjects were subjected to immunoprecipitation (IP) using anti-OGG1 and the isolated proteins probed for HNE, a by-product of lipid peroxidation (A). Nuclear specimens from 3 NC (lanes 1–2), 3 MCI (lanes 3–5), and 3 LAD subjects (lanes 6–8) were analyzed in the same way. Results of the assay show significantly more HNE-positive OGG1 in MCI mitochondrial specimens compared to NC specimens. HNE levels were not significantly different in nuclear immunoprecipitations.
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