Broad DNA repair responses in neural injury are associated with activation of the IL-6 pathway in cholesterol-fed rabbits.

Full Abstract

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.

Author information

Author/s: Wu, Min (M); Audet, Aaron (A); Cusic, Jenna (J); Seeger, Drew (D); Cochran, Richard (R); Ghribi, Othman (O);

Affiliation: Department of Biochemistry and Molecular Biology, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58203, USA. minwu(-atsign-)medicine.nodak.edu

Grants: ES014690 (Agency:NIEHS NIH HHS) ; P20 RR017699 (Agency:NCRR NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: Journal of neurochemistry (J Neurochem), published in England. (Language: eng)

Reference: 2009-Nov; vol 111 (issue 4) : pp 1011-21

Dates: Created 2009/10/23; Completed 2009/11/06;

PMID: 19765189, status: MEDLINE (last retrieval date: 11/6/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Alzheimer Disease - etiology; pathology
Animals
Cholesterol - administration & dosage; adverse effects; pharmacology
DNA Repair - physiology
Deoxyguanosine - analogs & derivatives; deficiency; metabolism
Disease Models, Animal
Female
Gene Expression Regulation - physiology
Hippocampus - metabolism; pathology

Hippocampus - metabolism; pathology
Interleukin-2 - metabolism
Mice
Mice, Knockout
Models, Biological
Neurons - drug effects; pathology
Rabbits
Signal Transduction - drug effects; physiology
Xeroderma Pigmentosum Group D Protein - metabolism

Associated Chemicals: Interleukin-2 (0) ; Cholesterol (57-88-5) ; 8-oxo-7-hydrodeoxyguanosine (88847-89-6) ; Deoxyguanosine (961-07-9) ; Xeroderma Pigmentosum Group D Protein (EC 5.99.-)

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