Broad DNA repair responses in neural injury are associated with activation of the IL-6 pathway in cholesterol-fed rabbits.
The importance of DNA repair in the pathogenic mechanism of Alzheimer's Disease (AD) is still poorly understood. Here, we report that a broad range of responses by DNA repair proteins plays a critical role in the regulation of inflammatory response in rabbits fed with cholesterol-rich diet, a model system for AD. We found accumulation of oxodG DNA adduct in the brain of rabbits fed with cholesterol-enriched diets compared to control diets, which subsequently induced a broad range of DNA repair protein activities. Also, the hippocampus was identified as the primary site of oxidative DNA damage and elevated OGG1 activity. In addition, a physical interaction between XPB and OGG1 may account for a potential mechanism involving these DNA repair responses. DNA repair proteins also impact activation of various signaling cascades, including Src in response to cholesterol oxidation. Furthermore, OGG1 deficient mice showed no IL-6 activation as seen in wt mice but a drastic increase of TNF-alpha, a pro-inflammatory cytokine. Thus, OGG1 may be associated with cytokine production induced by high cholesterol levels, impacting neurodegeneration. Together, our studies suggest that critical DNA repair proteins are associated with development of AD, and may serve as potential targets for the treatment of AD.
Wu
Min
M
Department of Biochemistry and Molecular Biology, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58203, USA. minwu@medicine.nodak.edu
Audet
Aaron
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Cusic
Jenna
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Seeger
Drew
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Cochran
Richard
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Ghribi
Othman
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D000080242:8-Hydroxy-2'-Deoxyguanosine; D000544:Alzheimer Disease / Q000209:etiology / Q000473:pathology*; D000818:Animals; D002784:Cholesterol / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D004260:DNA Repair / Q000502:physiology*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000172:deficiency / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D007376:Interleukin-2 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051759:Xeroderma Pigmentosum Group D Protein / Q000378:metabolism
D007376:Interleukin-2; D000080242:8-Hydroxy-2'-Deoxyguanosine; D002784:Cholesterol; D051759:Xeroderma Pigmentosum Group D Protein; D003849:Deoxyguanosine