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A neuronal DNA damage response is detected at the earliest stages of A lzheimer's neuropathology and correlates with cognitive impairment in the M edical R esearch C ouncil's C ognitive F unction and A geing S tudy ageing brain cohort
Author(s) -
Simpson Julie E.,
Ince Paul G.,
Matthews Fiona E.,
Shaw Pamela J.,
Heath Paul R.,
Brayne Carol,
Garwood Claire,
Higginbottom Adrian,
Wharton Stephen B.
Publication year - 2015
Publication title -
neuropathology and applied neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.538
H-Index - 95
eISSN - 1365-2990
pISSN - 0305-1846
DOI - 10.1111/nan.12202
Subject(s) - neuropathology , microbiology and biotechnology , biology , chemistry , medicine , disease , pathology
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 A lzheimer‐type neuropathology. Cumulative DNA damage and a reduced capacity of DNA repair may result in neuronal dysfunction and contribute to cognitive impairment independent of A lzheimer‐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 A lzheimer‐type pathology ( B raak & B raak stage 0– II ), and explored their relationship to cognitive impairment in a population‐representative sample from the M edical R esearch C ouncil's C ognitive F unction and A geing 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 M ini‐ M ental S tate E xamination 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.