192 Chapter 8 WM Development Leukodystrophies DAM signature PAM signature Phagocytosis Immune activation Lysosomal activity Immune Sensing Phagocytosis DAM signature Microglia Activation Immune Processing Phagocytosis Microglia activation Microgliosis DAM signature Lipid metabolism In ammatory signaling Lysosomal signaling WAM signature DAM signature Phagocytosis Immune function DAM signature Microgliosis Phagocytosis DAM signature Phagocytosis Immune activation DAM signature Phagocytosis Antigen presentation Ageing Neurodegeneration In ammation ALSP CSF1R NHD TREM2/TYROBP Pseudo-TORCH USP18 Demyelination Remyelination Time Figure 4. Heterogeneity of microglia in the white matter. Heterogeneity in white matter microglia is present from the early stages of development, as microglia states in the developing CNS show gene enrichment related to phagocytosis and proliferation. Mutations that impact on microglial function in the CNS give rise to leukodystrophies where microglia exhibit heterogeneity in their response depending on the mutation. During ageing, microglia states show similarities with disease associated microglia (DAM) that are also present in inflammation, neurodegeneration, demyelination and remyelination. Nevertheless, although similarities in gene enrichment are found in CNS diseases in which white matter is affected, many microglia states show distinct context-specific profiles and functions yet other functions may be equally important in influencing CNS health. Thirdly, ‘how stable are white matter microglial states?’ Understanding whether and/or how microglia are able to transition from one state to another could shed light on disease-triggering processes, and may point to potential therapeutic strategies to switch microglia state/function in disease. Fourthly, ‘how can we therapeutically target microglia states specifically, for instance in white matter disease, and detect the impact of drugs?’ The ease by which microglia adapt could prove to be beneficial for developing therapeutic strategies, either in alleviating disease progression by aiding white matter repair or restoration of homeostasis. In addition, development of targeting drug-encapsulating nanocapsules and microglia specific positron emission tomography tracers may facilitate therapeutic progress. In summary, the importance of microglia in white matter health together with the emerging importance of microglial states in CNS health and disease point to the importance of understanding the full spectrum and relevance of white matter microglia heterogeneity. 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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