SummaryMicroglia play key roles in brain development, homeostasis, and function, and it is widely assumed that the adult population is long lived and maintained by self-renewal. However, the precise temporal and spatial dynamics of the microglial population are unknown. We show in mice and humans that the turnover of microglia is remarkably fast, allowing the whole population to be renewed several times during a lifetime. The number of microglial cells remains steady from late postnatal stages until aging and is maintained by the spatial and temporal coupling of proliferation and apoptosis, as shown by pulse-chase studies, chronic in vivo imaging of microglia, and the use of mouse models of dysregulated apoptosis. Our results reveal that the microglial population is constantly and rapidly remodeled, expanding our understanding of its role in the maintenance of brain homeostasis.

Microglial proliferation and activation is a hallmark of Alzheimer’s disease. Olmos-Alonso et al. show that microglial proliferation in Alzheimer’s disease tissue correlates with overactivation of the colony-stimulating factor 1 receptor (CSF1R) pathway. CSF1R blockade arrests microglial proliferation and activation in a mouse model of Alzheimer-like pathology and slows disease progression.

The past decade has witnessed a revolution in our understanding of microglia. These immune cells were shown to actively remodel neuronal circuits, leading to propose new pathogenic mechanisms. To study microglial implication in the loss of synapses, the best pathological correlate of cognitive decline across chronic stress, aging, and diseases, we recently conducted ultrastructural analyses. Our work uncovered the existence of a new microglial phenotype that is rarely present under steady state conditions, in hippocampus, cerebral cortex, amygdala, and hypothalamus, but becomes abundant during chronic stress, aging, fractalkine signaling deficiency (CX3CR1 knockout mice), and Alzheimer's disease pathology (APP‐PS1 mice). Even though these cells display ultrastructural features of microglia, they are strikingly distinct from the other phenotypes described so far at the ultrastructural level. They exhibit several signs of oxidative stress, including a condensed, electron‐dense cytoplasm and nucleoplasm making them as “dark” as mitochondria, accompanied by a pronounced remodeling of their nuclear chromatin. Dark microglia appear to be much more active than the normal microglia, reaching for synaptic clefts, while extensively encircling axon terminals and dendritic spines with their highly ramified and thin processes. They stain for the myeloid cell markers IBA1 and GFP (in CX3CR1‐GFP mice), and strongly express CD11b and microglia‐specific 4D4 in their processes encircling synaptic elements, and TREM2 when they associate with amyloid plaques. Overall, these findings suggest that dark microglia, a new phenotype that we identified based on their unique properties, could play a significant role in the pathological remodeling of neuronal circuits, especially at synapses. GLIA 2016;64:826–839

Inflammation is a common neuropathological feature in several neurological disorders, including amyotrophic lateral sclerosis (ALS). We have studied the contribution of CSF1R signalling to inflammation in ALS, as a pathway previously reported to control the expansion and activation of microglial cells. We found that microglial cell proliferation in the spinal cord of SOD1G93A transgenic mice correlates with the expression of CSF1R and its ligand CSF1. Administration of GW2580, a selective CSF1R inhibitor, reduced microglial cell proliferation in SOD1G93A mice, indicating the importance of CSF1-CSF1R signalling in microgliosis in ALS. Moreover, GW2580 treatment slowed disease progression, attenuated motoneuron cell death and extended survival of SOD1G93A mice. Electrophysiological assessment revealed that GW2580 treatment protected skeletal muscle from denervation prior to its effects on microglial cells. We found that macrophages invaded the peripheral nerve of ALS mice before CSF1R-induced microgliosis occurred. Interestingly, treatment with GW2580 attenuated the influx of macrophages into the nerve, which was partly caused by the monocytopenia induced by CSF1R inhibition. Overall, our findings provide evidence that CSF1R signalling regulates inflammation in the central and peripheral nervous system in ALS, supporting therapeutic targeting of CSF1R in this disease.