189 White matter microglia heterogeneity Microglial activation has also been reported in other leukodystrophies121-123 such as in X-linked adrenoleukodystrophy (X-ALD) where prelesional areas with intact myelin are demarcated by loss of microglial TMEM119 and P2RY12 expression. Additionally, in metachromatic leukodystrophy (MLD) patches of amoeboid microglia that downregulate TMEM119 and P2RY12 show evidence of myelin phagocytosis in the normal appearing white matter (NAWM)121. Both MLD and X-ALD show overall loss of microglia and microglial death prior to major myelin breakdown121. Interestingly, there is a loss of microglial markers and altered microglial morphology in MLD, but not in X-ALD121. In Krabbe’s disease, also known as globoid cell leukodystrophy, microglia activation is the first pathological hallmark observed prior to astrocyte activation or oligodendrocyte pathology, possibly due to TLR2 mediated signalling123. Taken together, microglial activation has been implicated in driving pathology in several leukodystrophies through dysregulation of several pathways124. The regional and disease specific-manifestations might in future be explained by microglial heterogeneity. Neurodegenerative diseases The role of white matter microglia in neurodegenerative diseases is relatively understudied, as the main pathological hallmarks usually relate to neuronal cell bodies in the grey matter. One of the most prevalent neurodegenerative diseases is AD, characterized by deposition of extracellular amyloid-β plaques and intracellular tau tangles. AD is associated with genetic mutations in genes encoding for APP, PS1 and PS2 (early-onset AD; EOAD), or can occur sporadically (late-onset AD; LOAD). Neuroimaging studies have shown white matter changes associated with cognitive changes in EOAD, but whether white matter changes also occur in LOAD is still a matter of debate125-127. A role for microglia in AD has been implicated by genome wide association studies (GWAS)128, and microglia are affected particularly in relation to amyloid-β pathology129,130. The TgAPP21 rat model of AD does not spontaneously develop amyloid-β plaques but is vulnerable to plaque formation, making it an interesting model to study the pre-plaque phase. In this model, IBA1 immunoreactivity is increased in white matter tracts (corpus callosum, cingulum and internal capsule), correlated with impaired behavioral flexibility131, linking microglia with impairments of executive dysfunction prior to amyloid-β plaque formation. Similarly, in humans, increased IBA1 reactivity is present in the white matter of aged versus young individuals132. When comparing EOAD tissues with agematched controls, a similar increase in IBA1 activity was observed, but not in LOAD tissues. These data suggest that ageing and AD-related pathology may affect white matter microglia in a similar way, but that the combined effect is not additive. With the advent of single-cell/ nucleus RNA sequencing techniques, significant progress has been made in understanding the potential role of microglia in AD, both in mouse models and human brain tissue129,130,133. However, so far only studies using grey matter tissue129, or a mixture of cortical grey and white matter133, have been performed. Neuroinflammation and microglia have been increasingly implicated in the pathology of amyotrophic lateral sclerosis (ALS), characterised by progressive degeneration of motor neurons. ALS exists in a genetic form (fALS), often caused by mutations in C9orf72, SOD1, FUS or TARDBP, and a sporadic form (sALS). White matter damage in ALS may occur prior to the death of motor neurons134. Several bulk RNAseq studies of sALS tissue showed an enrichment of microglia gene expression in the ventral horn of the spinal cord135 and the motor cortex136. Several studies reported microgliosis in white matter of ALS and associated mouse models. In a SOD1 (G93A) mouse model of ALS, decreased grey and white matter volumes were
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