期刊
BRAIN PATHOLOGY
卷 25, 期 5, 页码 565-574出版社
WILEY
DOI: 10.1111/bpa.12216
关键词
dementia; DNA damage; ischemic white matter; white matter disease; white matter lesions
资金
- King Fahad Medical City, Saudi Arabia
- Medical Research Council [MR/J004308/1]
- Department of Health and the Medical Research Council [MRC/G9901400, MRC U.1052.00.0013]
- UK NIHR 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
- Oxford Biomedical Research Centre
- Walton Centre NHS Foundation Trust, Liverpool
- ARUK
- BBSRC
- Sheffield Teaching Hospitals NHS Foundation Trust
- Alzheimers Research UK [ART-PG2010-5] Funding Source: researchfish
- Biotechnology and Biological Sciences Research Council [BB/K006711/1] Funding Source: researchfish
- Medical Research Council [G9901400, MR/J004308/1, MC_U105292687, G1100540, MR/L016451/1, MR/L022656/1, G0900652, G0601022, G0502157, G0400074] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0611-10084] Funding Source: researchfish
- BBSRC [BB/K006711/1] Funding Source: UKRI
- MRC [G1100540, G0400074, G0502157, MR/J004308/1, G0601022, G0900652, G9901400, MR/L022656/1, MC_U105292687, MR/L016451/1] Funding Source: UKRI
White matter lesions (WML) are common in brain aging and are associated with dementia. We aimed to investigate whether oxidative DNA damage and occur in WML and in apparently normal white matter in cases with lesions. Tissue from WML and control white matter from brains with lesions (controls lesional) and without lesions (controls non-lesional) were obtained, using post-mortem magnetic resonance imaging-guided sampling, from the Medical Research Council Cognitive Function and Ageing Study. Oxidative damage was assessed by immunohistochemistry to 8-hydroxy-2'-deoxoguanosine (8-OHdG) and Western blotting for malondialdehyde. DNA response was assessed by phosphorylated histone H2AX (gamma H2AX), p53, senescence markers and by quantitative Reverse transcription polymerase chain reaction (RT-PCR) panel for candidate DNA damage-associated genes. 8-OHdG was expressed in glia and endothelium, with increased expression in both WML and controls lesional compared with controls non-lesional (P < 0.001). gamma H2Ax showed a similar, although attenuated difference among groups (P = 0.03). Expression of senescence-associated beta-galactosidase and p16 suggested induction of senescence mechanisms in glia. Oxidative DNA damage and a DNA damage response are features of WML pathogenesis and suggest candidate mechanisms for glial dysfunction. Their expression in apparently normal white matter in cases with WML suggests that white matter dysfunction is not restricted to lesions. The role of this field-effect lesion pathogenesis and cognitive impairment are areas to be defined.
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