186 Chapter 8 microglial datasets revealed that the WAMs were also present in these studies62,80. WAMs had depleted expression of microglial homeostatic genes, including P2ry12, Tmem119, Csf1r and Cx3cr1, and enriched expression of Apoe, Cd63 and Clec7a, some of which are associated with DAM and microglia in the developing white matter. Comparing genes that were differentially expressed in Cd11b+ cells (microglia and CNS-resident macrophages) in aged (21 month) versus young (4 month) mouse corpus callosum revealed that the top enriched pathways in aged white matter were related to immune cell function. WAM signature genes were present, including Spp1, Clec7a, Itgax and Apoe, again showing similarity to genes expressed by the developmental white matter state. Precisely when these pathway changes are initiated in white matter microglia with ageing is not known. Between 10-30% of IBA1+ cells in the corpus callosum expressed a WAMmarker (CLEC7A, AXL, LGALS3, Itgax) and notably, these cells were almost absent from the cortex. It is not clear, however, what proportion of the IBA1+ cells coexpress WAM markers, nor how many markers constitute a WAM state. WAM were found to group together in clusters or “nodules” of 3-5 cells, with distinctly thick processes and large cell bodies, reminiscent of previously documented microglia clusters considered to precede CNS demyelination in MS81. Using Trem2-/- mice and in vitro studies, WAMs were found to be involved in digestion of phagocytosed myelin debris, suggesting a protective function that avoids the build-up of degenerating myelin during ageing71. In several mouse models of AD, the WAM population appeared before the DAM state, and both states share part of their gene signature71. Interestingly, DAM rely on APOE for their development whereas WAM do not, indicating dissimilarities between the two states71. The conversion of WAM into DAM may be a mechanism by which normal brain ageing switches to a neurodegenerative state, with the WAM potentially pivoting from a protective function. Further work is required to understand if, why and how this conversion could occur. While it is still unclear whether DAM are protective or detrimental, elucidating the mechanisms underlying potential microglia state conversion represents a promising avenue to prevent disease in the ageing brain. Microglia heterogeneity in CNS diseases Inflammatory white matter diseases MS is a prototypical inflammatory white matter disease in which microglia are considered to contribute to myelin damage, and remyelination. Microglia activation and myelin loss also occur in the grey matter in MS82, preceding the neuronal and synaptic loss which are key determinants of disease progression83,84. The aetiology of MS and mechanisms leading to chronic disease likely involves interactions between environmental factors, the immune system, and neurons and glia. Studies in a model of autoimmune-mediated demyelination (experimental autoimmune encephalomyelitis- EAE) led to the widely held concept that MS is a T-cell-mediated disease, however, the efficacy of B-cell targeting (anti-CD20) therapies inMS has challenged this hypothesis85-88. Nevertheless, microglia are likely key players in MS lesion formation and MS disease progression. Studies using scRNA-seq and immunohistochemistry have identified a wide range of MS-associated microglia gene transcripts22,61,89. During EAE, microglia showed reduced expression of core signature genes P2RY12, Tmem119, and Selplg22. Jordao et al. identified four disease linked microglia states showing similarities with the DAM signature, and although all had reduced expression of P2RY12, Maf, and Slc2a5, differential up- and down-regulation of genes distinguished the disease-associated states, possibly related to stage of activation of microglia. Nevertheless, DAM did not change expression of the genes Olfml3 and Sparc, indicating that these might serve as robust markers of microglia in health and disease22. Microglia states related to de- and remyelination were
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