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Transcriptomic analysis of age-associated periventricular lesions reveals dysregulation of the immune response

Lookup NU author(s): Professor Fiona Matthews

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2020 by the authors. Licensee MDPI, Basel, Switzerland.White matter lesions (WML) are a common feature of the ageing brain associated with cognitive impairment. The gene expression profiles of periventricular lesions (PVL, n = 7) and radiologically-normal-appearing (control) periventricular white matter cases (n = 11) obtained from the Cognitive Function and Ageing Study (CFAS) neuropathology cohort were interrogated using microarray analysis and NanoString to identify novel mechanisms potentially underlying their formation. Histological characterisation of control white matter cases identified a subgroup (n = 4) which contained high levels of MHC-II immunoreactive microglia, and were classified as “pre-lesional.” Microarray analysis identified 2256 significantly differentially-expressed genes (p ≤ 0.05, FC ≥ 1.2) in PVL compared to non-lesional control white matter (1378 upregulated and 878 downregulated); 2649 significantly differentially-expressed genes in “pre-lesional” cases compared to PVL (1390 upregulated and 1259 downregulated); and 2398 significantly differentially-expressed genes in “pre-lesional” versus non-lesional control cases (1527 upregulated and 871 downregulated). Whilst histological evaluation of a single marker (MHC-II) implicates immune-activated microglia in lesion pathology, transcriptomic analysis indicates significant downregulation of a number of activated microglial markers and suggests established PVL are part of a continuous spectrum of white matter injury. The gene expression profile of “pre-lesional” periventricular white matter suggests upregulation of several signalling pathways may be a neuroprotective response to prevent the pathogenesis of PVL.


Publication metadata

Author(s): Fadul MM, Heath PR, Cooper-Knock J, Kurz JM, Al-Azzawi HA, Ali Z, Smith T, Matthews FE, Brayne C, Wharton SB, Simpson JE

Publication type: Article

Publication status: Published

Journal: International Journal of Molecular Sciences

Year: 2020

Volume: 21

Issue: 21

Pages: 1-21

Online publication date: 25/10/2020

Acceptance date: 23/10/2020

Date deposited: 09/11/2020

ISSN (print): 1661-6596

ISSN (electronic): 1422-0067

Publisher: MDPI AG

URL: https://doi.org/10.3390/ijms21217924

DOI: 10.3390/ijms21217924

PubMed id: 33113879


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