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Neuronal DNA damage response‐associated dysregulation of signalling pathways and cholesterol metabolism at the earliest stages of A lzheimer‐type pathology
Author(s) -
Simpson Julie E.,
Ince Paul G.,
Minett Thais,
Matthews Fiona E.,
Heath Paul R.,
Shaw Pamela J.,
Goodall Emily,
Garwood Claire J.,
Ratcliffe Laura E.,
Brayne Carol,
Rattray Magnus,
Wharton Stephen B.
Publication year - 2016
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.12252
Subject(s) - laser capture microdissection , biology , dna damage , transcriptome , alzheimer's disease , neurodegeneration , wnt signaling pathway , gsk 3 , cognitive decline , endocrinology , medicine , kinase , dementia , microbiology and biotechnology , signal transduction , disease , gene , gene expression , genetics , dna
Aims Oxidative damage and an associated DNA damage response ( DDR ) are evident in mild cognitive impairment and early A lzheimer's disease, suggesting that neuronal dysfunction resulting from oxidative DNA damage may account for some of the cognitive impairment not fully explained by A lzheimer‐type pathology. Methods Frontal cortex ( B raak stage 0– II ) was obtained from the M edical R esearch C ouncil's C ognitive F unction and A geing S tudy cohort. Neurones were isolated from eight cases (four high and four low DDR ) by laser capture microdissection and changes in the transcriptome identified by microarray analysis. Results Two thousand three hundred seventy‐eight genes were significantly differentially expressed (1690 up‐regulated, 688 down‐regulated, P < 0.001) in cases with a high neuronal DDR . Functional grouping identified dysregulation of cholesterol biosynthesis, insulin and W nt signalling, and up‐regulation of glycogen synthase kinase 3β. Candidate genes were validated by quantitative real‐time polymerase chain reaction. Cerebrospinal fluid levels of 24( S )‐hydroxycholesterol associated with neuronal DDR across all B raak stages ( r s = 0.30, P = 0.03). Conclusions A persistent neuronal DDR may result in increased cholesterol biosynthesis, impaired insulin and W nt signalling, and increased GSK 3 β , thereby contributing to neuronal dysfunction independent of A lzheimer‐type pathology in the ageing brain.