CSF1R inhibitors induce a sex-specific resilient microglial phenotype and functional rescue in a tauopathy mouse model

Noah R. Johnson, Peng Yuan, Erika Castillo, T. Peter Lopez, Weizhou Yue, Annalise Bond, Brianna M. Rivera, Miranda C. Sullivan, Masakazu Hirouchi, Kurt Giles, Atsushi Aoyagi and Carlo Condello ()
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Noah R. Johnson: University of California
Peng Yuan: University of California
Erika Castillo: University of California
T. Peter Lopez: University of California
Weizhou Yue: University of California
Annalise Bond: University of California
Brianna M. Rivera: University of California
Miranda C. Sullivan: University of California
Masakazu Hirouchi: University of California
Kurt Giles: University of California
Atsushi Aoyagi: University of California
Carlo Condello: University of California

Nature Communications, 2023, vol. 14, issue 1, 1-23

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-022-35753-w

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