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Nucleic Acids Research Advance Access published online on August 17, 2007
Nucleic Acids Research, doi:10.1093/nar/gkm605
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Molecular Biology

Defective DNA base excision repair in brain from individuals with Alzheimer's disease and amnestic mild cognitive impairment

Lior Weissman1, Dong-Gyu Jo2,3, Martin M. Sørensen1, Nadja C. de Souza-Pinto1, William R. Markesbery4, Mark P. Mattson2 and Vilhelm A. Bohr1,*

Laboratories of 1Molecular Gerontology, 2Neurosciences, National Institute on Aging, NIH, Baltimore, MD 21224, USA, 3College of Pharmacy, Sungkyunkwan University, Suwon, South Korea and 4Departments of Pathology and Laboratory Medicine, Neurology, and the Sanders-Brown Center on Aging and Alzheimer's Disease Center, University of Kentucky, Lexington, KY 40536, USA

*To whom correspondence should be addressed. Tel: +1 410 558 8162; Fax: +1 410 558 8157; Email: vbohr{at}nih.gov

Received June 20, 2007. Revised July 24, 2007. Accepted July 24, 2007.

Oxidative stress is thought to play a role in the pathogenesis of Alzheimer's disease (AD) and increased oxidative DNA damage has been observed in brain tissue from AD patients. Base excision repair (BER) is the primary DNA repair pathway for small base modifications such as alkylation, deamination and oxidation. In this study, we have investigated alterations in the BER capacity in brains of AD patients. We employed a set of functional assays to measure BER activities in brain tissue from short post-mortem interval autopsies of 10 sporadic AD patients and 10 age-matched controls. BER activities were also measured in brain samples from 9 amnestic mild cognitive impairment (MCI) subjects. We found significant BER deficiencies in brains of AD patients due to limited DNA base damage processing by DNA glycosylases and reduced DNA synthesis capacity by DNA polymerase ß. The BER impairment was not restricted to damaged brain regions and was also detected in the brains of amnestic MCI patients, where it correlated with the abundance of neurofibrillary tangles. These findings suggest that BER dysfunction is a general feature of AD brains which could occur at the earliest stages of the disease. The results support the hypothesis that defective BER may play an important role in the progression of AD.


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