Origins, properties, and therapeutic potential of cells that repopulate the micro

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DESCRIPTION (provided by applicant): Microglia are implicated in most disorders of the CNS, and while they offer protective roles in aspects of disease, their chronic activation and presence can impede recovery and promote cellular damage and cognitive decline. As such, anti-inflammatory strategies have been pursued as potential therapeutics to many neurodegenerative diseases, but have lacked potency. As part of our investigations into inflammation in the pathogenesis of Alzheimer's disease we targeted the colony-stimulating factor 1 receptor (CSF1R), as this regulates the proliferation of microglia. We discovered that microglia are actually physiologically dependent upon CSF1R signaling, and that administration of CSF1R antagonists results in the rapid and continued elimination of virtually all microglia from the CNS, without gross effects on peripheral macrophage populations. Mice lacking microglia, using this approach, are healthy, viable, and show no deleterious effects (we have treated for up to 3 months thus far). In CNS disease models we find that elimination of microglia is highly beneficial, suggesting that CSF1R antagonists could be an effective therapeutic for most CNS disorders. Crucially, CSF1R antagonists are in clinical trials for various cancers, and thus these findings are translatable. Our first aim is to track the fate of these eliminated microglia - do thy die with CSF1R inhibition, or do they dedifferentiate into a non-microglial cell? We have taken these findings further, to address the fundamental question of the regulation of microglia in the adult brain, by eliminating 99% of microglia via administration of CSF1R antagonists, and then withdrawing the antagonists to see if the microglia population could recover. Astonishingly, IBA-1 positive cells appear throughout the brain after just 3 days, with very different morphologies to resident microglia in control brains. These cells are also positive for CD45, nestin, Ki67 and stain with IB4. None of these markers are present in resident microglia in control brains. By 7 days, these cells have assumed similar morphologies to resident microglia, and these markers are absent once again. Thus, the adult brain has a highly plastic microglia population that can fully replenish itself when depleted, within days. Furthermore, we have identified a non- microglial cell that proliferates throughout the CNS and differentiates into the repopulating microglia - representing a potential microglia progenitor cell. This proposal seeks to further understand the origins of these "repopulating cells" and further characterize the transition of these potential microglia progenitor cells into microglia. In addition, we will look at the moleculr pathways that signal for repopulation of the microglia- depleted brain, and for differentiation int microglia, once present. Finally, we will assess the therapeutic potential of replacing "senescent" microglia in the aged brain with "repopulating" cells, and their ability to improve cognition and clear plaques in mouse models of Alzheimer's disease.