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Type 2 diabetes mellitus-associated transcriptome alterations in cortical neurones and associated neurovascular unit cells in the ageing brain

Bury, Joanna J.; Chambers, Annabelle; Heath, Paul R.; Ince, Paul G.; Shaw, Pamela J.; Matthews, Fiona E.; Brayne, Carol; Simpson, Julie E.; Wharton, Stephen B.

Authors

Joanna J. Bury

Annabelle Chambers

Paul R. Heath

Paul G. Ince

Pamela J. Shaw

Carol Brayne

Julie E. Simpson

Stephen B. Wharton



Abstract

Type 2 diabetes mellitus (T2D), characterised by peripheral insulin resistance, is a risk factor for dementia. In addition to its contribution to small and large vessel disease, T2D may directly damage cells of the brain neurovascular unit. In this study, we investigated the transcriptomic changes in cortical neurones, and associated astrocytes and endothelial cells of the neurovascular unit, in the ageing brain. Neurone, astrocyte, and endothelial cell-enriched mRNA, obtained by immuno-laser capture microdissection of temporal cortex (Brodmann area 21/22) from 6 cases with self-reported T2D in the Cognitive Function and Ageing Study neuropathology cohort, and an equal number of age and sex-matched controls, was assessed by microarray analysis. Integrated Molecular Pathway Level Analysis was performed using the Kyoto Encyclopaedia of Genes and Genomes database on significantly differentially expressed genes, defined as P < 0.05 and fold-change ± 1.2. Hub genes identified from Weighted Gene Co-expression Network Analysis were validated in neurones using the NanoString nCounter platform. The expression and cellular localisation of proteins encoded by selected candidate genes were confirmed by immunohistochemistry. 912, 2202, and 1227 genes were significantly differentially expressed between cases with self-reported T2D and controls in neurones, astrocytes, and endothelial cells respectively. Changes in cortical neurones included alterations in insulin and other signalling pathways, cell cycle, cellular senescence, inflammatory mediators, and components of the mitochondrial respiratory electron transport chain. Impaired insulin signalling was shared by neurovascular unit cells with, additionally, apoptotic pathway changes in astrocytes and dysregulation of advanced glycation end-product signalling in endothelial cells. Transcriptomic analysis identified changes in key cellular pathways associated with T2D that may contribute to neuronal damage and dysfunction. These effects on brain cells potentially contribute to a diabetic dementia, and may provide novel approaches for therapeutic intervention.

Citation

Bury, J. J., Chambers, A., Heath, P. R., Ince, P. G., Shaw, P. J., Matthews, F. E., …Wharton, S. B. (2021). Type 2 diabetes mellitus-associated transcriptome alterations in cortical neurones and associated neurovascular unit cells in the ageing brain. Acta Neuropathologica Communications, 9(1), Article 5. https://doi.org/10.1186/s40478-020-01109-y

Journal Article Type Article
Acceptance Date Dec 15, 2020
Online Publication Date Jan 6, 2021
Publication Date Jan 6, 2021
Deposit Date Mar 31, 2024
Publicly Available Date Apr 3, 2024
Journal Acta Neuropathologica Communications
Electronic ISSN 2051-5960
Publisher BioMed Central
Peer Reviewed Peer Reviewed
Volume 9
Issue 1
Article Number 5
DOI https://doi.org/10.1186/s40478-020-01109-y
Keywords Ageing; Cortical neurone; Dementia; Differential expression; Neurovascular unit; Transcriptome; Type 2 diabetes mellitus
Public URL https://hull-repository.worktribe.com/output/4451222

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http://creativecommons.org/licenses/by/4.0

Copyright Statement
© The Author(s) 2021.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.




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