13 General introduction type and a decrease in tight junction proteins. These changes that are also observed during ageing41 may explain the increase in susceptibility to neuroinflammation and neurodegenerative disorders in the elderly. Microglia and macrophages Historically microglia have been described as the phagocytes of the CNS, however over the last decades microglia are increasingly implicated in exerting diverse roles. Microglia comprise roughly 10% of the glial population in the CNS but unlike astrocytes or oligodendrocytes, microglia are derived from the yolk sac from which they migrate and populate the brain during embryonic development42. Microglia are highly motile and versatile cells, they self-renew, through proliferation, and upon damage or injury can increase their population by clonal expansion43. This clonal expansion is directed by cues from the micro-environment and results in microglia numbers that are dependent on the local need43. Activated microglia are often seen as drivers for neuropathology44, however, loss of vital homeostatic functions of microglia has also been linked with leukodystrophies, characterised by progressive myelin damage. Initially, microglia were classified as being either classically activated (M1) or alternatively activated (M2), based on chemokine and cytokine expression in vivo45. More recently the field has switched to account for a plethora of microglial states recognising the microglial heterogeneity that is present within the brain parenchyma in health and disease. Several reports indicate that microglia have different transcriptomic profiles dependent on the region of the brain, the stage of development and age46, neuropathological state47, and the microbiome48 (Figure 2). NEURODEGENERATION INFLAMMATION HOMEOSTASIS AGEING DEVELOPMENT REGION MYELINATION Switching between microglial states is vital for processes such as remyelination and is affected by ageing49. Microglia secrete pro-inflammatory as well as anti-inflammatory factors which can either be beneficial or detrimental in neurodegenerative diseases50, for example microglia depletion in a mouse model of AD reduced neuronal loss without affecting β-amyloid pathology51. Additionally, microglia-derived factors such as blood derived neurotrophic Figure 2. Kaleidoscope of microglia heterogeneity. Microglia are highly heterogeneous and can adapt to any function that is needed for the local environment which is different in health when it is compared to neuroinflammation, remyelination, as well as neurodegeneration. Additionally, microglia are influenced by extrinsic factors such as ageing, the stage of development, or the region where they reside.
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