Microglia are resident macrophages of the central nervous system that have key functions in its development, homeostasis and response to damage and infection. Although microglia have been increasingly implicated in contributing to the pathology that underpins neurological dysfunction and disease, they also have crucial roles in neurological homeostasis and regeneration. This includes regulation of the maintenance and regeneration of myelin, the membrane that surrounds neuronal axons, which is required for axonal health and function. Myelin is damaged with normal ageing and in several neurodegenerative diseases, such as multiple sclerosis and Alzheimer disease. Given the lack of approved therapies targeting myelin maintenance or regeneration, it is imperative to understand the mechanisms by which microglia support and restore myelin health to identify potential therapeutic approaches. However, the mechanisms by which microglia regulate myelin loss or integrity are still being uncovered. In this Review, we discuss recent work that reveals the changes in white matter with ageing and neurodegenerative disease, how this relates to microglia dynamics during myelin damage and regeneration, and factors that influence the regenerative functions of microglia.
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S.A.K. discloses support for this work from the Wellcome Trust Translational Neuroscience PhD Programme (108890/Z/15/Z) at The University of Edinburgh. V.E.M. discloses support for this work from the John David Eaton Chair in Multiple Sclerosis Research (St Michael’s Hospital Foundation and Barlo MS Centre) and a Medical Research Council Senior Non-Clinical Fellowship.
V.E.M. currently receives research funds from Astex Pharmaceuticals relating to some of the topics covered in this Review. S.A.K. declares no competing interests.
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- 3×Tg mouse model of Alzheimer disease
Mice that harbour the human APP transgene containing the Swedish mutation, a PSEN1 knock-in with the M146V mutation and the MAPT transgene containing the P301L mutation. Unlike some of the other commonly used Alzheimer disease mouse models, this model progressively develops both amyloid-β plaques and neurofibrillary tangles, with extracellular amyloid-β deposited at 6 months of age and hyperphosphorylated tau aggregates observed at 12–15 months of age. These mice exhibit synaptic dysfunction before the detection of plaques and tangles, and cognitive impairment is seen at 4 months of age.
- App NL-G-F mouse model of Alzheimer disease
Mice that possess a single amyloid-β precursor protein gene (APP) knock-in, containing a humanized amyloid-β domain with three mutations, namely the Swedish ‘NL’, Arctic ‘G’ and Iberian ‘F’ mutations. Although APP is expressed at wild-type levels, the NL, G and F mutations boost total amyloid-β production, encourage amyloid-β aggregation and increase the amyloid-β42:amyloid-β40 ratio, respectively. These mice exhibit amyloid-β plaque accumulation with deposition beginning at 2 months of age. They also display microgliosis, astrocytosis and synapse loss, in addition to cognitive impairment at 6 months of age. Neurofibrillary tangles are absent from this model.
- APP/PS1 mouse model of Alzheimer disease
Mice that express two human transgenes for APP and PSEN1 (presenilin-1, also known as PS1), which contain the Swedish and L166P mutations, respectively. Both are under the control of the Thy1 promoter, and the mice demonstrate overexpression of APP with levels approximately threefold higher than those endogenously expressed. Amyloid-β deposition begins at 6 weeks of age, with microgliosis and astrocytosis, and dendritic spine loss is also observed in the mice. Cognitive impairment is seen at 7 months of age, and neurofibrillary tangles are absent from this model.
- Border-associated macrophages
Also known as central nervous system (CNS)-associated macrophages, these macrophages reside in the border regions of the CNS including the perivascular spaces, the choroid plexus and the meninges.
- Dietary cuprizone-induced demyelination
In this model, mice are fed with the copper chelator cuprizone, leading to oligodendrocyte death and subsequent demyelination followed by spontaneous remyelination, which is initiated during the late demyelination phase and continues robustly over the subsequent 3–6 weeks after withdrawal of cuprizone.
- Lysophosphatidylcholine (LPC)-induced demyelination
A widely used model to study remyelination, involving injection of LPC to induce focal demyelination in either the corpus callosum or spinal cord, which is typically complete by 3 days after injection and is followed by robust remyelination without ongoing demyelination over the subsequent 2–4 weeks.
Monocytes originate from haematopoietic stem and progenitor cells in the bone marrow, from which they emigrate to circulate in the blood before entering tissues and differentiating into either macrophages or monocyte-derived dendritic cells.
- PDGF–APP Sw.Ind mouse model of Alzheimer disease
Mice that express the human APP transgene containing the Swedish and Indiana (V717F) mutations, under the control of the PDGFB promoter. These mice overexpress APP, with amyloid-β seen at 6 weeks of age and plaques evident at 5–7 months of age. This model also demonstrates synapse loss, astrogliosis and microgliosis, in addition to cognitive deficits by 4 months of age. Neurofibrillary tangles are absent from this model.
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Kent, S.A., Miron, V.E. Microglia regulation of central nervous system myelin health and regeneration. Nat Rev Immunol (2023). https://doi.org/10.1038/s41577-023-00907-4
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