Oxidative Glial Cell Damage Associated with White Matter Lesions in the Ageing Human Brain.

Brain pathology (Zurich, Switzerland)

PubMedID: 25311358

Al-Mashhadi S, Simpson J, Heath P, Dickman M, Forster G, Matthews FE, Brayne C, Ince P, Wharton S, MRC-CFAS. Oxidative Glial Cell Damage Associated with White Matter Lesions in the Ageing Human Brain. Brain Pathol. 2014;.
White matter lesions (WML) are common in brain ageing 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 MRI-guided sampling, from the MRC Cognitive Function and Ageing Study. Oxidative damage was assessed by immunohistochemistry to 8 hydroxy deoxoguanosine (8-OHdG) and western blotting for malondialdehyde. DNA response was assessed by ?H2Ax, p53, senescence markers and by quantitative 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 to controls non-lesional (p<0.001). ?H2Ax showed a similar, though attenuated difference between groups (p=0.03). Expression of senescence-associated ß-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.