These authors contributed equally.
Broad DNA repair responses in neural injury are associated with activation of the IL-6 pathway in cholesterol-fed rabbits
Version of Record online: 18 SEP 2009
© 2009 The Authors. Journal Compilation © 2009 International Society for Neurochemistry
Journal of Neurochemistry
Volume 111, Issue 4, pages 1011–1021, November 2009
How to Cite
Wu, M., Audet, A., Cusic, J., Seeger, D., Cochran, R. and Ghribi, O. (2009), Broad DNA repair responses in neural injury are associated with activation of the IL-6 pathway in cholesterol-fed rabbits. Journal of Neurochemistry, 111: 1011–1021. doi: 10.1111/j.1471-4159.2009.06390.x
- Issue online: 16 OCT 2009
- Version of Record online: 18 SEP 2009
- Received June 26, 2009; revised manuscript received August 30, 2009; accepted September 7, 2009.
- Alzheimer’s disease;
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-α, 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.