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DNA damage response and senescence in endothelial cells of human cerebral cortex and relation to A lzheimer's neuropathology progression: a population‐based study in the M edical R esearch C ouncil C ognitive F unction and A geing S tudy ( MRC ‐ CFAS ) cohort
Author(s) -
Garwood Claire J.,
Simpson Julie E.,
Al Mashhadi Sufana,
Axe Claire,
Wilson Suzanna,
Heath Pamela R.,
Shaw Pamela J.,
Matthews Fiona E.,
Brayne Carol,
Ince Paul G.,
Wharton Stephen B.
Publication year - 2014
Publication title -
neuropathology and applied neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.538
H-Index - 95
eISSN - 1365-2990
pISSN - 0305-1846
DOI - 10.1111/nan.12156
Subject(s) - neuropathology , dna damage , senescence , biology , pathology , population , alzheimer's disease , microbiology and biotechnology , dna , medicine , disease , genetics , environmental health
Aims Abnormalities of the brain microvasculature in A lzheimer'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 A lzheimer‐type neuropathology we investigated DNA damage in a population‐based sample derived from the M edical R esearch C ouncil C ognitive F unction and A geing S tudy. Methods We examined endothelial damage in frontal and temporal cortex ( n = 97) using immunohistochemistry for γ H 2 AX and DNA –protein kinase ( DNA ‐ PK cs). To determine the effects of endothelial DNA damage at the earliest stages of A lzheimer's pathology we further focused our analysis on cases classified as B raak 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 ). Results We demonstrated large variation in endothelial DNA damage which was not associated with A lzheimer's neuropathology. Endothelial DNA ‐ PK cs correlated with neuronal and glial DNA ‐ PK cs counts. Focusing our further analysis on B raak 0– II cases, qPCR analysis demonstrated a trend to increased TP 53 ( 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 ‐ PK cs expression. Conclusions Damage to brain endothelial cells occurs early in relation to, or independently of, A lzheimer 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.