190 Chapter 8 observed in the spinal cords in association with increased apoptosis, astrogliosis and microgliosis137. In the human corticospinal tract in ALS, microgliosis correlated with axonal loss in white matter adjacent to the motor cortex, being most pronounced in cases with fast disease progression138. Spatial transcriptomics showed enrichment of a gene expression module relating to microglia homeostasis in the white matter of control and presymptomatic SOD1 mice compared to the terminal end stage disease of both ALS and SOD1 mice72. At end stage disease in mice, a reactive microglial gene expression module was also enriched in the grey matter, yet was attenuated in the white matter of the spinal cord, although microgliaassociated changes in ALS spinal cord were not reported. In C9orf72-/- mice, another mouse model of ALS, expression of genes associated with activated microglia (DAM-like) were downregulated, while expression of interferon associated genes were upregulated139. These changes did not result in differential abundance of microglia states, indicating that the gene expression differences observed did not drive microglial heterogeneity. Microglia in a double transgenic mouse model, C9orf72-/- and amyloid-β (5xFAD), showed enhanced engagement with and clearance of plaques, but also enhanced synaptic pruning resulting in memory deficits and neuronal injury. These data suggest that microglia in C9orf72-/- mice have both beneficial and detrimental functions in the context of neurodegeneration. However, whether these changes are associated with white or grey matter microglia is not yet known. Taken together, these studies reveal that white matter microglia are affected and contribute to neurodegenerative diseases such as AD and ALS. Although heterogeneity of microglia has been identified in the grey matter, further research is needed to establish the presence and contribution of white matter microglia heterogeneity in these diseases. Therapeutic approaches Despite the implication of microglia in CNS pathology and repair, there are no approved therapies specifically aimed at targeting microglia behaviour for the treatment of neurological conditionsordisease. Thismayreflect inpart thechallenge imposedbymicroglial heterogeneity in state and function, and the missing link between the two. Drug development is further complicated by the dynamic changes microglia undergo over time following CNS insult, as observed during white matter damage and repair55,61,62,140. Nonetheless, pre-clinical studies have revealed several promising therapeutic strategies which regulate microglia function in the white matter. For instance, phagocytosis of myelin debris by microglia consequent to demyelination is required for efficient remyelination, and is encouraged in microglia/ macrophages by in vivo exposure to vitamin B3 (niacin)141, an agonist of retinoid-X-receptors (RXR)142, and immuno-modulatory drugs (fingolimod, glatiramer acetate)143. Promotion of myelin debris clearance and remyelination has also been achieved through increased physical activity following demyelination144, pointing to exercise as a potential drug-free treatment strategy. In addition, dampening the microglial pro-inflammatory responses that occur with ageing anddiseasemay prevent neural cell damage. The expressionof inflammatorymediators by microglia/macrophages is reduced by treatment with the antibiotic minocycline, the mood disorder drug quetiapine fumarate, and the muscarinic receptor antagonist clemastine, the latter currently being trialled for its ability to promote remyelination143. Another potential therapeutic option is the replacement of damaging microglia for restoration of normal microglia function. For instance, in MS, the reduced remyelination
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