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 i s 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.

Public Health Relevance

We have discovered that microglia are physiologically dependent upon CSF1R signaling for their survival. We can take advantage of this dependency and eliminate virtually all microglia from the adult brain, by the administration of CSF1R antagonists. While we can keep microglia eliminated indefinitely, through continuous treatment with CSF1R antagonists, we have found that new cells can completely repopulate the brain when treatment is stopped. These cells rapidly appear and differentiate into new microglia. This proposal seeks to understand the source and properties of these new cells, and whether they can be utilized as a potential therapeutic for Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS083801-01A1
Application #
8695963
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Corriveau, Roderick A
Project Start
2014-02-15
Project End
2019-01-31
Budget Start
2014-02-15
Budget End
2015-01-31
Support Year
1
Fiscal Year
2014
Total Cost
$322,515
Indirect Cost
$103,765
Name
University of California Irvine
Department
Other Basic Sciences
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697