Aims: Population-based studies have shown that approximately 20% of the ageing population (aged 65 years and over) with dementia have little or no classical Alzheimer-type neuropathology. Cumulative DNA damage and a reduced capacity of DNA repair may result in neuronal dysfunction and contribute to cognitive impairment independent of Alzheimer-type pathology in the ageing brain.
Methods: We investigated expression of the DNA damage response (DDR)-associated molecules γH2AX and DNA-PKcs using immunohistochemistry and western blotting, and senescence-associated β-galactosidase in the frontal association neocortex of cases with low levels of Alzheimer-type pathology (Braak & Braak stage 0-II), and explored their relationship to cognitive impairment in a population-representative sample from the Medical Research Council's Cognitive Function and Ageing Study cohort.
Results: Increases in both γH2AX(+) (r(s) = -0.36, P = 0.025) and DNA-PKcs(+) (r(s) = -0.39, P = 0.01) neuronal counts were associated with a lower Mini-Mental State Examination score. Increasing levels of senescence associated-β-gal(+) pyramidal neurones were weakly associated with the total number of DNA-PKcs(+) neurones (P = 0.08), but not with traditional senescence-associated signalling molecules, including p53 and p16.
Conclusion: The association between the neuronal DDR and cognitive impairment, independent of AD pathology in the ageing brain, may be suggestive of a causal link via neuronal dysfunction.
Keywords: DNA damage response; DNA-PKcs; cognitive impairment; neurone; γH2AX.
© 2014 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.