Neuronal DNA damage response‐associated dysregulation of signalling pathways and cholesterol metabolism at the earliest stages of Alzheimer‐type pathology

Julie E Simpson,The Mrc Cognitive Function And Ageing Neuropathology Study Group ,Carol Brayne,Paul R Heath,Laura E Ratcliffe,Thais Minett,Emily Goodall,Stephen B Wharton,Claire J Garwood,Pamela J Shaw,Fiona E Matthews,Magnus Rattray,Paul G Ince

doi:10.1111/nan.12252

Abstract

AimsOxidative 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.MethodsFrontal 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.ResultsTwo 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 (r s = 0.30, P = 0.03).ConclusionsA 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.

Highlights

Having demonstrated the population variation in the neuronal DNA damage response (DDR) in individuals with little or no Alzheimertype pathology and the association with cognitive impairment [8], this study aimed to identify the gene expression changes associated with the neuronal DDR, which may contribute to neuronal dysfunction in the ageing brain
We have previously demonstrated an association between the neuronal DDR and cognitive impairment in cases with little or no Alzheimer’s neuropathology, and shown that high levels of a neuronal DDR correlate with lower Mini Mental State Examination (MMSE) scores [8]
Suggesting post-transcriptional regulation of Wnt expression. Both insulin/IGF and Wnt signalling negatively regulate the activity of GSK3β [39], expression of which was significantly up-regulated in cases with a high neuronal DDR

Summary

Introduction

Population-based studies have shown that age-associated cognitive decline often occurs in individuals with low levels of either classical Alzheimer-type neuropathology. Previous investigation of the Medical Research Council’s Cognitive Function and Ageing Study (MRC CFAS) cohort has demonstrated high levels of oxidative stress and an associated DDR occur at the earliest stages of Alzheimer pathology [6], as defined by low Braak and Braak neurofibrillary tangle stage [7], and an increased neuronal DDR at these early pathological stages is associated with cognitive impairment and neuronal senescence [8]. These population-based approaches have the potential to identify new biomarkers and therapeutic strategies [12,13]

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Results

Conclusion