Abstract
In the inflammatory demyelinating neurodegenerative disease multiple sclerosis (MS), there is increasing interest in gray matter pathology, as neuronal loss and cortical atrophy correlate with disability and disease progression, and MS therapeutics fail to significantly slow or stop neurodegeneration. Microglia, the central nervous system (CNS)-resident macrophages, are extensively involved in white matter MS pathology, but are also implicated in gray matter pathology, similar to other neurodegenerative diseases, for which there is synaptic, axonal, and neuronal degeneration. Microglia display regional heterogeneity within the CNS, which reflects their highly plastic nature and their ability to deliver context-dependent responses tailored to the demands of their microenvironment. Therefore, microglial roles in the MS gray matter in part reflect and in part diverge from those in the white matter. The present review summarizes current knowledge of microglial involvement in gray matter changes in MS, in demyelination, synaptic damage, and neurodegeneration, with evidence implicating microglia in pathology, neuroprotection, and repair. As our understanding of microglial physiology and pathophysiology increases, we describe how we are moving toward potential therapeutic applications in MS, harnessing microglia to protect and regenerate the CNS.
Highlights
The majority of the knowledge regarding microglial involvement in multiple sclerosis (MS) pathology comes from studying the white matter of MS patients and animal models
The development of novel tools that distinguish between microglia and non-parenchymal central nervous system (CNS) macrophages[6] is likely to uncover their functions in MS gray matter in the future
Gray matter pathology in multiple sclerosis is of great current interest as recent advances in live brain imaging reveal that this is present from the earliest disease stages, and, unlike white matter pathology, is significantly correlated with disability
Summary
The majority of the knowledge regarding microglial involvement in multiple sclerosis (MS) pathology comes from studying the white matter of MS patients and animal models. Some features of gray matter pathology in MS are distinct from those typical to the white matter,[2] which might require or dictate different microglial responses. Both detrimental and beneficial roles have been reported for microglia in the literature, due to their highly plastic nature, allowing them to deliver tailored context-dependent responses. This review will present evidence supporting both damaging and beneficial microglial functions and underscore the highly complex interplay between pathological and restorative processes in MS gray matter. The development of novel tools that distinguish between microglia and non-parenchymal CNS macrophages[6] is likely to uncover their functions in MS gray matter in the future. Demyelination can be repaired to some extent by the restoration of lost myelin sheaths around axons, termed remyelination; on the contrary, neurodegeneration in the gray matter appears irreversible, is prominent from the earliest stages of MS and is the substrate of a large proportion of permanent disability experienced by MS patients.[11,12] existing disease-modifying treatments can reduce white matter lesion load but seem rather
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
