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White matter microglia heterogeneity in the CNS

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Abstract

Microglia, the resident myeloid cells in the central nervous system (CNS) play critical roles in shaping the brain during development, responding to invading pathogens, and clearing tissue debris or aberrant protein aggregations during ageing and neurodegeneration. The original concept that like macrophages, microglia are either damaging (pro-inflammatory) or regenerative (anti-inflammatory) has been updated to a kaleidoscope view of microglia phenotypes reflecting their wide-ranging roles in maintaining homeostasis in the CNS and, their contribution to CNS diseases, as well as aiding repair. The use of new technologies including single cell/nucleus RNA sequencing has led to the identification of many novel microglia states, allowing for a better understanding of their complexity and distinguishing regional variations in the CNS. This has also revealed differences between species and diseases, and between microglia and other myeloid cells in the CNS. However, most of the data on microglia heterogeneity have been generated on cells isolated from the cortex or whole brain, whereas white matter changes and differences between white and grey matter have been relatively understudied. Considering the importance of microglia in regulating white matter health, we provide a brief update on the current knowledge of microglia heterogeneity in the white matter, how microglia are important for the development of the CNS, and how microglial ageing affects CNS white matter homeostasis. We discuss how microglia are intricately linked to the classical white matter diseases such as multiple sclerosis and genetic white matter diseases, and their putative roles in neurodegenerative diseases in which white matter is also affected. Understanding the wide variety of microglial functions in the white matter may provide the basis for microglial targeted therapies for CNS diseases.

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Acknowledgements

We thank Prof. Dr. M.S. van der Knaap, Prof. Dr. N. Wolf., and Dr. M. Bugiani for supplying tissue from ALSP and MLD for the pathology figure.

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Authors and Affiliations

  1. Department of Pathology, Amsterdam UMC–Location VUmc, Amsterdam, The Netherlands

    Sandra Amor, Manuel C. Marzin & Erik Nutma

  2. Department of Neuroscience and Trauma, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK

    Sandra Amor

  3. United Kingdom Dementia Research Institute at The University of Edinburgh, Centre for Discovery Brain Sciences, Chancellor’s Building, Edinburgh, UK

    Niamh B. McNamara & Veronique E. Miron

  4. Medical Research Council Centre for Reproductive Health, The Queen’s Medical Research Institute, The University of Edinburgh, Edinburgh, UK

    Niamh B. McNamara & Veronique E. Miron

  5. Department of Biomedical Sciences of Cells and Systems, Section Molecular Neurobiology, University of Groningen and University Medical Center Groningen (UMCG), Groningen, The Netherlands

    Emma Gerrits & Susanne M. Kooistra

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S.A., N.B.M., E.G., M.M., S.K., V.E.M. and E.N. researched data for the article, and wrote the manuscript. All authors reviewed, edited and agreed on the content of the manuscript before submission.

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Amor, S., McNamara, N.B., Gerrits, E. et al. White matter microglia heterogeneity in the CNS. Acta Neuropathol 143, 125–141 (2022). https://doi.org/10.1007/s00401-021-02389-x

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