# Origins, properties, and therapeutic potential of cells that repopulate the microglia-depleted adult brain

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2023 · $373,512

## Abstract

Abstract:
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.

## Key facts

- **NIH application ID:** 10554378
- **Project number:** 5R01NS083801-10
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Kim Green
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $373,512
- **Award type:** 5
- **Project period:** 2014-02-15 → 2024-09-18

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10554378

## Citation

> US National Institutes of Health, RePORTER application 10554378, Origins, properties, and therapeutic potential of cells that repopulate the microglia-depleted adult brain (5R01NS083801-10). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10554378. Licensed CC0.

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