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The Microglial Transcriptome of Age-Associated Deep Subcortical White Matter Lesions Suggests a Neuroprotective Response to Blood-Brain Barrier Dysfunction

Almansouri, Taghreed ; Waller, Rachel ; Wharton, Stephen B ; Heath, Paul R ; Matthews, Fiona E ; Brayne, Carol ; van Eeden, Fredericus ; Simpson, Julie E

MDPI AG 2024

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  • Título:
    The Microglial Transcriptome of Age-Associated Deep Subcortical White Matter Lesions Suggests a Neuroprotective Response to Blood-Brain Barrier Dysfunction
  • Autor: Almansouri, Taghreed ; Waller, Rachel ; Wharton, Stephen B ; Heath, Paul R ; Matthews, Fiona E ; Brayne, Carol ; van Eeden, Fredericus ; Simpson, Julie E
  • Assuntos: Aged ; Aged, 80 and over ; Aging ; Antigens, CD ; Antigens, Differentiation, Myelomonocytic ; Blood-Brain Barrier ; deep subcortical lesions ; Female ; Gene Expression Profiling ; Humans ; Male ; microglia ; Neuroprotection ; Transcriptome ; transcriptomic profiling ; White Matter
  • Descrição: Peer reviewed: True Acknowledgements: CFAS would like to acknowledge the essential contribution of the liaison officers, the general practitioners, their staff, and nursing and residential home staff. We are grateful to our respondents and their families for their generous gift to medical research, which has made this study possible. Publication status: Published Funder: King Abdulaziz University Funder: UK NIHR Biomedical Research Centre Funder: NIHR Cambridge Biomedical Research Centre Funder: Nottingham University Hospitals NHS Trust Funder: University of Sheffield, Sheffield Teaching Hospitals NHS Foundation Trust and the Sheffield NIHR Biomedical Research Centre Funder: Oxford Biomedical Research Centre Funder: Walton Centre NHS Foundation Trust Age-associated deep-subcortical white matter lesions (DSCLs) are an independent risk factor for dementia, displaying high levels of CD68+ microglia. This study aimed to characterize the transcriptomic profile of microglia in DSCLs and surrounding radiologically normal-appearing white matter (NAWM) compared to non-lesional control white matter. CD68+ microglia were isolated from white matter groups (n = 4 cases per group) from the Cognitive Function and Ageing Study neuropathology cohort using immuno-laser capture microdissection. Microarray gene expression profiling, but not RNA-sequencing, was found to be compatible with immuno-LCM-ed post-mortem material in the CFAS cohort and identified significantly differentially expressed genes (DEGs). Functional grouping and pathway analysis were assessed using the Database for Annotation Visualization and Integrated Discovery (DAVID) software, and immunohistochemistry was performed to validate gene expression changes at the protein level. Transcriptomic profiling of microglia in DSCLs compared to non-lesional control white matter identified 181 significant DEGs (93 upregulated and 88 downregulated). Functional clustering analysis in DAVID revealed dysregulation of haptoglobin-haemoglobin binding (Enrichment score 2.5, p = 0.017), confirmed using CD163 immunostaining, suggesting a neuroprotective microglial response to blood-brain barrier dysfunction in DSCLs. In NAWM versus control white matter, microglia exhibited 347 DEGs (209 upregulated, 138 downregulated), with significant dysregulation of protein de-ubiquitination (Enrichment score 5.14, p < 0.001), implying an inability to maintain protein homeostasis in NAWM that may contribute to lesion spread. These findings enhance understanding of microglial transcriptomic changes in ageing white matter pathology, highlighting a neuroprotective adaptation in DSCLs microglia and a potentially lesion-promoting phenotype in NAWM microglia.
  • Editor: MDPI AG
  • Data de criação/publicação: 2024
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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