Cargando…
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...
Autores principales: | , , , , , , , , , , , |
---|---|
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 |
_version_ | 1784867557234180096 |
---|---|
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. |
format | Online Article Text |
id | pubmed-9829908 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT johnsonnoahr csf1rinhibitorsinduceasexspecificresilientmicroglialphenotypeandfunctionalrescueinatauopathymousemodel AT yuanpeng csf1rinhibitorsinduceasexspecificresilientmicroglialphenotypeandfunctionalrescueinatauopathymousemodel AT castilloerika csf1rinhibitorsinduceasexspecificresilientmicroglialphenotypeandfunctionalrescueinatauopathymousemodel AT lopeztpeter csf1rinhibitorsinduceasexspecificresilientmicroglialphenotypeandfunctionalrescueinatauopathymousemodel AT yueweizhou csf1rinhibitorsinduceasexspecificresilientmicroglialphenotypeandfunctionalrescueinatauopathymousemodel AT bondannalise csf1rinhibitorsinduceasexspecificresilientmicroglialphenotypeandfunctionalrescueinatauopathymousemodel AT riverabriannam csf1rinhibitorsinduceasexspecificresilientmicroglialphenotypeandfunctionalrescueinatauopathymousemodel AT sullivanmirandac csf1rinhibitorsinduceasexspecificresilientmicroglialphenotypeandfunctionalrescueinatauopathymousemodel AT hirouchimasakazu csf1rinhibitorsinduceasexspecificresilientmicroglialphenotypeandfunctionalrescueinatauopathymousemodel AT gileskurt csf1rinhibitorsinduceasexspecificresilientmicroglialphenotypeandfunctionalrescueinatauopathymousemodel AT aoyagiatsushi csf1rinhibitorsinduceasexspecificresilientmicroglialphenotypeandfunctionalrescueinatauopathymousemodel AT condellocarlo csf1rinhibitorsinduceasexspecificresilientmicroglialphenotypeandfunctionalrescueinatauopathymousemodel |