We discovered microglia in the adult brain are dependent on signaling through the colony-stimulating factor 1 receptor (CSF1R), and identified several CSF1R inhibitors that crossed into the brain, leading to the elimination of most of the microglia. This remarkable phenomenon has been widely replicated and is now a standard in the field to explore microglial function in health and disease, and clinical trials are being conducted/planned as a result. We also found that we could eliminate microglia for as long as we continued treatment, but upon drug withdrawal, repopulation of the microglial tissue occurred rapidly from proliferating cells throughout the brain that formed a new microglial tissue in ~14 days. We found we could use this to ?reset? the inflamed microglial tissue after injury or in aging, and promote functional recovery/cognition. In this continuation, we seek to understand the source and properties of these repopulating cells that become microglia, and study how they modulate neuronal gene expression to rejuvenate the aged brain and fully restore long-term potentiation to that of a young animal. In addition, we describe a second slower source of microglial repopulation, that originates in specific brain niches ? the rostral migratory stream (RMS) and associated projecting axonal tracts. This ?alternative? repopulation is only unmasked by the complete elimination of microglia. These ?alternative? cells arise from unknown cells within these brain niches, and eventually can break out from the white matter tracts and fill the cortex/brain. These cells never attain the numbers, morphologies, or gene expression of microglia, but resemble microglia found in the RMS, which have pro-neurogenesis and increased phagocytotic capabilities than other microglia. We will determine the source of these ?alternative? cells, and the consequences of filling the brain with them, including if they have any therapeutic potential, in a mouse model of Alzheimer's disease.

Public Health Relevance

Our prior work has resulted in the ability to eliminate all microglia from the brain, via clinically utilized CSF1R inhibitors, and to then repopulate the microglia-depleted brain with new cells that become a new microglial tissue, following CSF1R inhibitor withdrawal. We have identified 2 separate routes of microglial repopulation ? a rapid ?regular? repopulation that occurs from surviving microglia and unidentified brain-wide proliferating cells, and a slower ?alternative? repopulation that occurs from unidentified cells appearing at specific brain niches along the rostral migratory stream and associated projecting axonal tracts, that resemble microglia that first accumulate there in post-natal development. We will identify the cellular sources of both of these repopulation routes, and explore the consequences of filling the brain with ?alternative? microglia on brain homeostasis and progression of Alzheimer's disease; additionally, we will explore the mechanism by which repopulation rejuvenates the aged brain and fully restores long-term potentiation to that of a young animal.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS083801-06
Application #
9596877
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Corriveau, Roderick A
Project Start
2014-02-15
Project End
2024-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
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
92617
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