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Updated: Aug 14, 2025
Cell-based Assay to Study Antibody-mediated Tau Clearance by Microglia
Published on: November 9, 2018
CSF1R inhibitors induce a sex-specific resilient microglial phenotype and functional rescue in a tauopathy mouse
Noah R Johnson1,2,3, Peng Yuan1,4, Erika Castillo1
1Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, 94158, USA.
Abstract:
Microglia are central to pathogenesis in many neurological conditions. Drugs targeting colony-stimulating factor-1 receptor (CSF1R) to block microglial proliferation in preclinical disease models have shown mixed outcomes, thus the therapeutic potential of this approach remains unclear. Here, we show that CSF1R inhibitors given by multiple dosing paradigms in the Tg2541 tauopathy mouse model cause a sex-independent reduction in pathogenic tau and reversion of non-microglial gene expression patterns toward a normal wild type signature. Despite greater drug exposure in male mice, only female mice have functional rescue and extended survival. A dose-dependent upregulation of immediate early genes and neurotransmitter dysregulation are observed in the brains of male mice only, indicating that excitotoxicity may preclude functional benefits. Drug-resilient microglia in male mice exhibit morphological and gene expression patterns consistent with increased neuroinflammatory signaling, suggesting a mechanistic basis for sex-specific excitotoxicity. Complete microglial ablation is neither required nor desirable for neuroprotection and therapeutics targeting microglia must consider sex-dependent effects.
Insights
Targeting colony-stimulating factor-1 receptor (CSF1R) shows promise for neurological diseases, but benefits are sex-specific. While reducing tau pathology, CSF1R inhibitors caused excitotoxicity in males, highlighting the need to consider sex-dependent effects in microglial therapeutics.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Microglia play a key role in neurological disease pathogenesis.
- Colony-stimulating factor-1 receptor (CSF1R) inhibitors are being investigated for microglial-targeted therapies, but their efficacy is uncertain.
- Preclinical studies show mixed outcomes for CSF1R inhibitors in neurological disease models.
Purpose of the Study:
- To investigate the therapeutic potential of CSF1R inhibitors in a mouse model of tauopathy.
- To determine the sex-specific effects of CSF1R inhibition on disease progression and survival.
- To elucidate the mechanisms underlying potential sex differences in response to CSF1R inhibitors.
Main Methods:
- Utilized the Tg2541 mouse model of tauopathy.
- Administered CSF1R inhibitors using various dosing strategies.
- Assessed changes in pathogenic tau levels, gene expression patterns, and microglial characteristics.
- Analyzed functional outcomes, survival rates, and neurochemical changes, with a focus on sex-specific differences.
Main Results:
- CSF1R inhibition reduced pathogenic tau and normalized gene expression in a sex-independent manner.
- Female mice showed functional rescue and extended survival, despite lower drug exposure compared to males.
- Male mice exhibited dose-dependent immediate early gene upregulation and neurotransmitter dysregulation, suggesting excitotoxicity.
- Drug-resilient microglia in males displayed heightened neuroinflammatory signaling, correlating with sex-specific excitotoxicity.
Conclusions:
- CSF1R inhibitors can reduce tau pathology but elicit sex-specific functional outcomes.
- Excitotoxicity in male mice, potentially mediated by drug-resilient microglia, limits therapeutic benefits.
- Complete microglial ablation is not necessary for neuroprotection; sex-dependent effects must be considered for microglial-targeted therapeutics.
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