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Increased DNA Oxidation and Decreased Levels of Repair Products in Alzheimer's Disease Ventricular CSF
Author(s) -
Lovell Mark A.,
Gabbita S. Prasad,
Markesbery William R.
Publication year - 1999
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1999.0720771.x
Subject(s) - alzheimer's disease , disease , dna , medicine , chemistry , endocrinology , biochemistry
: One of the leading etiologic hypotheses regardingAlzheimer's disease (AD) is the involvement of free radical‐mediated oxidativestress in neuronal degeneration. Although several recent studies show anincrease in levels of brain DNA oxidation in both aging and AD, there havebeen no studies of levels of markers of DNA oxidation in ventricular CSF. Thisis a study of levels of 8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG), thepredominant marker of oxidative DNA damage, in intact DNA and as the“free” repair product that results from repair mechanisms. Free8‐OHdG was isolated from CSF from nine AD and five age‐matched controlsubjects using solidphase extraction columns and measured using gaschromatography/mass spectrometry with selective ion monitoring. Intact DNA wasisolated from the same samples and the levels of 8‐OHdG determined in theintact structures. Quantification of results was carried out using stableisotope‐labeled 8‐OHdG. By using this sensitive methodology, statisticallysignificant elevations ( p < 0.05) of 8‐OHdG were observed inintact DNA in AD subjects compared with age‐matched control subjects. Incontrast, levels of free 8‐OHdG, removed via repair mechanisms, were depletedsignificantly in AD samples ( p < 0.05). Our results demonstrate an increase in unrepaired oxygen radical‐mediated damage in AD DNA as evidenced by the increased presence of 8‐OHdG in intact DNA and decreased concentrations of the free repair product. These data suggest that the brain in AD may be subject to the double insult of increased oxidative stress, as well as deficiencies in repair mechanisms responsible for removal of oxidized bases.