γH2AX is increased in peripheral blood lymphocytes of Alzheimer’s disease patients in the South Australian Neurodegeneration, Nutrition and DNA Damage (SAND) study of aging

Abstract

An early cellular response to DNA double-strand breaks is the phosphorylation of histone H2AX to form γH2AX. Although increased levels of γH2AX have been reported in neuronal nuclei of Alzheimer’s disease (AD) patients, γH2AX responses in the lymphocytes of individuals with mild cognitive impairment (MCI) and AD remain unexplored. In this study, the endogenous γH2AX level was measured, using laser scanning cytometry (LSC) and visual scoring, in lymphocyte nuclei from MCI (n = 18), or AD (n = 20) patients and healthy controls (n = 40). Levels were significantly elevated in nuclei of the AD group compared to the MCI and control groups, and there was a concomitant increase, with a significant trend, from the control group through MCI to the AD group. A significant negative correlation was seen between γH2AX and the mini mental state examination (MMSE) score, when the analysis included all subjects. Receiver Operation Characteristic curves were carried out for different γH2AX parameters; visually scored percent cells containing overlapping γH2AX foci displayed the best area under the curve value of 0.9081 with 85% sensitivity and 92% specificity for the identification of AD patients versus control. Plasma homocysteine, creatinine, and chitinase-3-like protein 1 (CHI3L1) were positively correlated with lymphocyte γH2AX signals, while glomerular filtration rate (GFR) was negatively correlated. Finally, there was a diminished γH2AX response to X-rays in lymphocytes of the MCI and AD groups compared to the control group. Our results indicate that lymphocyte γH2AX levels are a potential marker for identifying individuals at increased risk of developing AD. Prospective studies with normal healthy individuals are needed to test whether there is indeed a link between γH2AX levels and AD risk.