TY - JOUR T1 - CSF1R inhibitor levels determine sex-specific phenotype of resilient microglia and neurofunctional rescue leading to extended survival in tauopathy mice JF - bioRxiv DO - 10.1101/2021.03.20.436288 SP - 2021.03.20.436288 AU - Noah R. Johnson AU - Peng Yuan AU - Erika Castillo AU - T. Peter Lopez AU - Weizhou Yue AU - Annalise Bond AU - Brianna M. Rivera AU - Miranda C. Sullivan AU - Masakazu Hirouchi AU - Kurt Giles AU - Atsushi Aoyagi AU - Carlo Condello Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/06/19/2021.03.20.436288.abstract N2 - 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, CSF1R inhibitors were evaluated in tauopathy mice using multiple dosing schemes, drug analogs, and longitudinal measurements in the brain and plasma. A sex-independent reduction in pathogenic tau was seen in several models and non-microglial gene expression patterns reverted toward a normal wild type signature. Surprisingly, despite greater drug exposure in male mice, functional rescue and extended survival was only observed in female mice. A dose-dependent upregulation of immediate early genes was observed in male mice only, indicating excitotoxicity that may have precluded functional benefits. Drug-resilient microglia in male mice exhibited morphological and gene expression patterns consistent with increased neuroinflammatory signaling, suggesting a mechanistic basis for sex-specific excitotoxicity. These data argue that complete microglial ablation is neither required nor desirable for neuroprotection and that therapeutics targeting microglia must consider sex-dependent effects on functional outcomes.Competing Interest StatementThe Institute for Neurodegenerative Diseases (UCSF) had a research collaboration with Daiichi Sankyo, Inc. (Tokyo, Japan). ER -