Open AccessOxidative Glial Cell Damage Associated with White Matter Lesions in the Aging Human Brain
Author(s) -
AlMashhadi Sufana,
Simpson Julie E.,
Heath Paul R.,
Dickman Mark,
Forster Gillian,
Matthews Fiona E.,
Brayne Carol,
Ince Paul G.,
Wharton Stephen B.
Publication year - 2015
Publication title -
brain pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.986
H-Index - 132
eISSN - 1750-3639
pISSN - 1015-6305
DOI - 10.1111/bpa.12216
Subject(s) - dna damage , white matter , senescence , pathology , pathogenesis , hyperintensity , lesion , oxidative stress , biology , immunohistochemistry , brain damage , medicine , magnetic resonance imaging , endocrinology , dna , biochemistry , radiology
Abstract 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 M edical R esearch C ouncil C ognitive F unction and A geing S tudy. Oxidative damage was assessed by immunohistochemistry to 8‐hydroxy‐2′‐deoxoguanosine (8‐ OHdG ) and W estern blotting for malondialdehyde. DNA response was assessed by phosphorylated histone H2AX ( γH2AX ), p 53, 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). γH2Ax showed a similar, although attenuated difference among groups ( P = 0.03). Expression of senescence‐associated β ‐galactosidase and p 16 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.