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

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 sho...

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Autores principales: Johnson, Noah R., Yuan, Peng, Castillo, Erika, Lopez, T. Peter, Yue, Weizhou, Bond, Annalise, Rivera, Brianna M., Sullivan, Miranda C., Hirouchi, Masakazu, Giles, Kurt, Aoyagi, Atsushi, Condello, Carlo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9829908/
https://www.ncbi.nlm.nih.gov/pubmed/36624100
http://dx.doi.org/10.1038/s41467-022-35753-w
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author Johnson, Noah R.
Yuan, Peng
Castillo, Erika
Lopez, T. Peter
Yue, Weizhou
Bond, Annalise
Rivera, Brianna M.
Sullivan, Miranda C.
Hirouchi, Masakazu
Giles, Kurt
Aoyagi, Atsushi
Condello, Carlo
author_facet Johnson, Noah R.
Yuan, Peng
Castillo, Erika
Lopez, T. Peter
Yue, Weizhou
Bond, Annalise
Rivera, Brianna M.
Sullivan, Miranda C.
Hirouchi, Masakazu
Giles, Kurt
Aoyagi, Atsushi
Condello, Carlo
author_sort Johnson, Noah R.
collection PubMed
description 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.
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spelling pubmed-98299082023-01-11 CSF1R inhibitors induce a sex-specific resilient microglial phenotype and functional rescue in a tauopathy mouse model Johnson, Noah R. Yuan, Peng Castillo, Erika Lopez, T. Peter Yue, Weizhou Bond, Annalise Rivera, Brianna M. Sullivan, Miranda C. Hirouchi, Masakazu Giles, Kurt Aoyagi, Atsushi Condello, Carlo Nat Commun Article 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. Nature Publishing Group UK 2023-01-09 /pmc/articles/PMC9829908/ /pubmed/36624100 http://dx.doi.org/10.1038/s41467-022-35753-w Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Johnson, Noah R.
Yuan, Peng
Castillo, Erika
Lopez, T. Peter
Yue, Weizhou
Bond, Annalise
Rivera, Brianna M.
Sullivan, Miranda C.
Hirouchi, Masakazu
Giles, Kurt
Aoyagi, Atsushi
Condello, Carlo
CSF1R inhibitors induce a sex-specific resilient microglial phenotype and functional rescue in a tauopathy mouse model
title CSF1R inhibitors induce a sex-specific resilient microglial phenotype and functional rescue in a tauopathy mouse model
title_full CSF1R inhibitors induce a sex-specific resilient microglial phenotype and functional rescue in a tauopathy mouse model
title_fullStr CSF1R inhibitors induce a sex-specific resilient microglial phenotype and functional rescue in a tauopathy mouse model
title_full_unstemmed CSF1R inhibitors induce a sex-specific resilient microglial phenotype and functional rescue in a tauopathy mouse model
title_short CSF1R inhibitors induce a sex-specific resilient microglial phenotype and functional rescue in a tauopathy mouse model
title_sort csf1r inhibitors induce a sex-specific resilient microglial phenotype and functional rescue in a tauopathy mouse model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9829908/
https://www.ncbi.nlm.nih.gov/pubmed/36624100
http://dx.doi.org/10.1038/s41467-022-35753-w
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