185 White matter microglia heterogeneity developing white matter is unclear. However, there is an overlap in genes expressed by both microglial states including Spp1, Apoe, and Lpl, which are also expressed by DAMs and are re-expressed following white matter injury30,46,62,63. Similarly, Ccl4-expressing microglia peak at P5 and are expanded in the ageing mouse brain and following demyelination in the mouse and in humans62. DAM signatures were also found in the developing human foetal CNS, and increasingly resemble adult homeostatic microglia throughout development63. Importantly, shared expression of one or several genes does not necessarily translate to function. For instance, CD11c+ microglia that re-emerge in the adult CNS following autoimmune-mediated demyelination have a distinct gene signature to neonatal CD11c+microglia, indicating that this marker may be expressed by distinct microglial states throughout the lifespan74. Nevertheless, Hammond and colleagues found that while microglia are most diverse in the developing brain and this diversity decreases in adulthood, they become more heterogeneous again in the aged or injured brain62. Ageing A plethora of studies support microglia heterogeneity in the ageing and diseased CNS. Microglia in the aged brain are characterised by expression of inflammatory genes, including chemokines Ccl3 and Ccl4, Cst7 and IL1b62,75, and those involved in immunoregulatory function, such as the interferon pathway54,62,76. In human microglia, ageing induces downregulation of genes associated with TGF-β signalling, suggesting a reduction in their homeostatic signature, while amyloid fibre formation pathway-associated genes are upregulated77. Grabert et al. reported regional heterogeneity in mouse microglia ageing profiles, with cerebellar microglia showing accelerated ageing in their transcriptomic signature compared to other brain regions54. This raises the important question of the effect of ageing on microglia in the white matter specifically. While the majority of studies involved sequencing of microglia from the whole brain, a recent report shed light on microglia heterogeneity in the ageing white matter69. Sankowski et al. compared human microglia in grey versus white matter of the temporal lobe across various ages, by combining scRNA-sequencing and multiplexed mass cytometry (cyTOF). Microglia in the white matter showed enriched expression of HLA-DR, CD68 and APOE compared to grey matter microglia, pointing to differential roles in antigen presentation, phagocytosis and cholesterol transport. Interestingly, an increase in osteopontin+ (SPP1+) microglia/ macrophages (IBA1+) during ageing was reported, with higher percentages in the white matter compared to grey matter69,75. SPP1 is a pro-inflammatory cytokine upregulated by microglia in aged mice and mouse models of AD78, although its precise function remains unclear in this context. Heterogeneity of microglia specifically in the aged mouse white matter was reported using two sequencing approaches, SmartSeq2 for higher gene depth and Drop-Seq for greater cell coverage, revealing four major microglia populations in the white matter of 18–24-monthold mice71. Two homeostatic microglial states were found in both grey and white matter, and two populations were exclusive to white matter: an activated microglia cluster and ‘white matter-associated microglia’ (referred to as WAMs). Both white matter-specific states were dependent on TREM2 for their development, in common with the previously identified DAM population. TREM2 signalling is also required for driving macrophage cell states outside of the CNS, for example in lipid-associated macrophages (LAM)79, which may point to roles of DAM and WAM in lipid metabolism. Reanalysis of previously published scRNA-seq aged mouse
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