Increased Nuclear DNA Oxidation in the Brain in Alzheimer's Disease

Authors

  • S. Prasad Gabbita,

    1. Sanders-Brown Center on Aging and Alzheimer's Disease Research Center,
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  • Mark A. Lovell,

    1. Sanders-Brown Center on Aging and Alzheimer's Disease Research Center,
    2. Departments of Chemistry,
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  • William R. Markesbery

    Corresponding author
    1. Sanders-Brown Center on Aging and Alzheimer's Disease Research Center,
    2. Neurology, and
    3. Pathology, University of Kentucky, Lexington, Kentucky, U.S.A.
      Address correspondence and reprint requests to Dr. W. R. Markesbery at 101 Sanders-Brown Bldg., University of Kentucky, Lexington, KY 40536-0230, U.S.A.
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Address correspondence and reprint requests to Dr. W. R. Markesbery at 101 Sanders-Brown Bldg., University of Kentucky, Lexington, KY 40536-0230, U.S.A.

Abstract

Abstract: Multiple lines of evidence indicate that oxidative stress is a contributor to neuronal death in Alzheimer's disease (AD). The oxidative damage that occurs to DNA may play a role in both normal aging and neurodegenerative diseases, including AD. This is a study of the oxidative damage that occurs in nuclear DNA in the brains of AD patients and cognitively intact, prospectively evaluated, age-matched control subjects. Nuclear DNA from frontal, temporal, and parietal lobes and cerebellum was isolated from 11 control subjects and 9 AD subjects, and oxidized purine and pyrimidine bases were quantitated using gas chromatography/mass spectrometry. Stable isotope-labeled oxidized base analogues were used as internal standards to measure 5-hydroxyuracil, 5-hydroxycytosine, 8-hydroxyadenine, 4,6-diamino-5-formamidopyrimidine (Fapy-adenine), 8-hydroxyguanine, and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (Fapy-guanine). Statistically significant elevations of 5-hydroxycytosine, 5-hydroxyuracil, 8-hydroxyadenine, and 8-hydroxyguanine were found in AD brain compared with control subjects (p < 0.05). There was an increased trend in the levels of Fapy-adenine in the AD brain, and Fapy-guanine showed a trend toward higher levels in control brains compared with AD. A generally higher level of oxidative DNA damage was present in neocortical regions than cerebellum. No significant correlation was observed between the oxidized bases and neurofibrillary tangle and senile plaque counts. Our results demonstrate that nuclear DNA damage by oxygen-derived radicals is increased in AD and support the concept that the brain is under increased oxidative stress in AD.

Abbreviations used: AD, Alzheimer's disease; BSTFA, N,O-bis-(trimethylsilyl)trifluoroacetamide; Fapy-adenine, 4,6-diamino-5-formamidopyrimidine; Fapy-guanine, 2,6-diamino-4-hydroxy-5-formamidopyrimidine; GC/MS, gas chromatography/mass spectrometry; NFT, neurofibrillary tangle; 8-OHdG, 8-hydroxy-2′-deoxyguanosine; PMI, postmortem interval; SP, senile plaque.

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