DNA damage response and senescence in endothelial cells of human cerebral cortex and relation to Alzheimer's neuropathology progression: a population-based study in the Medical Research Council Cognitive Function and Ageing Study (MRC-CFAS) cohort
Abnormalities of the brain microvasculature in Alzheimer's disease have led to the vascular hypothesis of the disease, which predicts that vascular changes precede neuronal dysfunction and degeneration. To determine the spectrum of endothelial injury in the elderly and its relation to Alzheimer-type neuropathology we investigated DNA damage in a population-based sample derived from the Medical Research Council Cognitive Function and Ageing Study.
We examined endothelial damage in frontal and temporal cortex (n = 97) using immunohistochemistry for γH2AX and DNA–protein kinase (DNA-PKcs). To determine the effects of endothelial DNA damage at the earliest stages of Alzheimer's pathology we further focused our analysis on cases classified as Braak 0–II and examined endothelial senescence using histochemistry for β-galactosidase and the expression of genes related to DNA damage and senescence using quantitative polymerase chain reaction (qPCR).
We demonstrated large variation in endothelial DNA damage which was not associated with Alzheimer's neuropathology. Endothelial DNA-PKcs correlated with neuronal and glial DNA-PKcs counts. Focusing our further analysis on Braak 0–II cases, qPCR analysis demonstrated a trend to increased TP53 (P = 0.064) in cases with high compared with low endothelial DNA damage which was supported by immunohistochemical analysis of p53. Endothelial β-galactosidase expression was associated with increased neuronal (P = 0.033) and glial (P = 0.038), but not endothelial DNA-PKcs expression.
Damage to brain endothelial cells occurs early in relation to, or independently of, Alzheimer pathology, and parallels that in neurones and glia. Endothelial DNA damage and senescence are a brain ageing process that may contribute to dysfunction of the neurovascular unit in some elderly individuals.