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
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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+ (rs = −0.36, P = 0.025) and DNA‐PKcs+ (rs = −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.
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DSB marker proteins correlate with cognitive impairment in individuals with low levels of amyloid and tau pathology.
“Similarly, DSB marker proteins correlate with cognitive impairment in individuals with low levels of amyloid and tau pathology (Simpson et al, 2015).”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Simpson et al, 2015
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Early neuronal accumulation of DNA double strand breaks in Alzheimer’s disease
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- Authors
- Simpson, J. E., Ince, P. G., Matthews, F. E., Shaw, P. J., Heath, P. R., Brayne, C., Garwood, C., Higginbottom, A., Wharton, S. B., & MRC Cognitive Function and Ageing Neuropathology Study Group
- Affiliations
- University of Sheffield (GB)
- University of Cambridge (GB)
- Corresponding author
- Wharton, Stephen B.
- ORCID
- Venue
- Neuropathology and Applied Neurobiology
- Publisher
- Wiley
- Published
- 2015-04-23
- Volume
- 41
- Issue
- 4
- Pages
- 483-496
- ISSN
- 0305-1846 (ISSN-L)
- 1365-2990
- PMC
- PMC4861215
- OpenAlex
- W1494866131
- Cited by
- 56
- References
- 53
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 4 · 2023: 6 · 2022: 5 · 2021: 4 · 2020: 8 · 2019: 7 · 2018: 4 · 2017: 4 · 2016: 5 · 2015: 2
- FWCI
- 2.80
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neuropathology and Applied Neurobiology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Repository@Hull (Worktribe) (University of Hull) (submittedVersion, cc-by)
- Funders
- Department of Health
- Medical Research Council (MRC/G9901400, MRC U.1052.00.0013, MR/J004 308/1)
- UKNIHR Biomedical Research Centre for Ageing and Age-related Disease Award
- NIHR Cambridge Biomedical Research Centre
- Cambridgeshire and Peterborough NIHR CLAHRC
- Nottingham University Hospitals NHS Trust
- University of Sheffield
- Sheffield Teaching Hospitals NHS Foundation Trust
- Oxford Biomedical Research Centre
- Walton Centre NHS Foundation Trust, Liverpool
- Neurocare
- Alzheimer's Research UK (ART-PG2010-5)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- Alzheimer's disease, DNA damage response, γH2AX, DNA-PKcs, cognitive impairment, neuronal senescence, senescence-associated β-galactosidase, Braak stages, brain aging, dementia, frontal association cortex, pyramidal neurons, neuronal dysfunction
- MeSH terms
- Aged, Aged, 80 and over, Aging, Alzheimer Disease, Brain, DNA Damage, Female, Histones, Humans, Male, Neurons, Neuropsychological Tests, Protein Kinases, Cohort Studies, Pyramidal Cells, Oxidative Stress
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