title: Neuronal DNA damage response-associated dysregulation of signalling pathways and cholesterol metabolism at the earliest stages of Alzheimer-type pathology.
abstract: OBJECTIVE
  Oxidative damage and an associated DNA damage response (DDR) are evident in mild cognitive impairment and early Alzheimer's disease, suggesting that neuronal dysfunction resulting from oxidative DNA damage may account for some of the cognitive impairment not fully explained by Alzheimer-type pathology.
  
  
  METHODS
  Frontal cortex (Braak stage 0-II) was obtained from the Medical Research Council's Cognitive Function and Ageing Study 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 Wnt 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 Braak stages (rs  = 0.30, P = 0.03).
  
  
  CONCLUSIONS
  A persistent neuronal DDR may result in increased cholesterol biosynthesis, impaired insulin and Wnt signalling, and increased GSK3β, thereby contributing to neuronal dysfunction independent of Alzheimer-type pathology in the ageing brain.
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Simpson
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ince
authors.affiliation: Institute of Public Health, University of Cambridge, Cambridge, UK.|Department of Radiology, University of Cambridge, Cambridge, UK.
authors.forename: Thais
authors.initials: T
authors.lastname: Minett
authors.affiliation: MRC Biostatistics Unit, Institute of Public Health, Cambridge, UK.|Institute of Health and Society, University of Newcastle, Newcastle, UK.
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Matthews
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Heath
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Shaw
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
authors.forename: Emily
authors.initials: E
authors.lastname: Goodall
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
authors.forename: Claire J
authors.initials: CJ
authors.lastname: Garwood
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Ratcliffe
authors.affiliation: Institute of Public Health, University of Cambridge, Cambridge, UK.
authors.forename: Carol
authors.initials: C
authors.lastname: Brayne
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.|Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors.forename: Magnus
authors.initials: M
authors.lastname: Rattray
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Wharton
mesh_terms: D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002784:Cholesterol / Q000378:metabolism*; D004249:DNA Damage / Q000502:physiology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D061346:Laser Capture Microdissection; D008297:Male; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D059467:Transcriptome
chemical_list: D002784:Cholesterol
keywords: Ageing brain; Alzheimer's; DNA damage response; dementia; microarray; neurones