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Pharmacological modulation of TSPO in microglia/macrophages and neurons in a chronic neurodegenerative model of prion disease

Neuroinflammation is an important component of many neurodegenerative diseases, whether as a primary cause or a secondary outcome. For that reason, either as diagnostic tools or to monitor progression and/or pharmacological interventions, there is a need for robust biomarkers of neuroinflammation in...

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Autores principales: Vicente-Rodríguez, Marta, Mancuso, Renzo, Peris-Yague, Alba, Simmons, Camilla, Gómez-Nicola, Diego, Perry, V. Hugh, Turkheimer, Federico, Lovestone, Simon, Parker, Christine A., Cash, Diana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10084680/
https://www.ncbi.nlm.nih.gov/pubmed/37032328
http://dx.doi.org/10.1186/s12974-023-02769-y
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author Vicente-Rodríguez, Marta
Mancuso, Renzo
Peris-Yague, Alba
Simmons, Camilla
Gómez-Nicola, Diego
Perry, V. Hugh
Turkheimer, Federico
Lovestone, Simon
Parker, Christine A.
Cash, Diana
author_facet Vicente-Rodríguez, Marta
Mancuso, Renzo
Peris-Yague, Alba
Simmons, Camilla
Gómez-Nicola, Diego
Perry, V. Hugh
Turkheimer, Federico
Lovestone, Simon
Parker, Christine A.
Cash, Diana
author_sort Vicente-Rodríguez, Marta
collection PubMed
description Neuroinflammation is an important component of many neurodegenerative diseases, whether as a primary cause or a secondary outcome. For that reason, either as diagnostic tools or to monitor progression and/or pharmacological interventions, there is a need for robust biomarkers of neuroinflammation in the brain. Mitochondrial TSPO (18 kDa Translocator protein) is one of few available biomarkers of neuroinflammation for which there are clinically available PET imaging agents. In this study, we further characterised neuroinflammation in a mouse model of prion-induced chronic neurodegeneration (ME7) including a pharmacological intervention via a CSF1R inhibitor. This was achieved by autoradiographic binding of the second-generation TSPO tracer, [3H]PBR28, along with a more comprehensive examination of the cellular contributors to the TSPO signal changes by immunohistochemistry. We observed regional increases of TSPO in the ME7 mouse brains, particularly in the hippocampus, cortex and thalamus. This increased TSPO signal was detected in the cells of microglia/macrophage lineage as well as in astrocytes, endothelial cells and neurons. Importantly, we show that the selective CSF1R inhibitor, JNJ-40346527 (JNJ527), attenuated the disease-dependent increase in TSPO signal, particularly in the dentate gyrus of the hippocampus, where JNJ527 attenuated the number of Iba1+ microglia and neurons, but not GFAP+ astrocytes or endothelial cells. These findings suggest that [3H]PBR28 quantitative autoradiography in combination with immunohistochemistry are important translational tools for detecting and quantifying neuroinflammation, and its treatments, in neurodegenerative disease. Furthermore, we demonstrate that although TSPO overexpression in the ME7 brains was driven by various cell types, the therapeutic effect of the CSF1R inhibitor was primarily to modulate TSPO expression in microglia and neurons, which identifies an important route of biological action of this particular CSF1R inhibitor and provides an example of a cell-specific effect of this type of therapeutic agent on the neuroinflammatory process. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-023-02769-y.
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spelling pubmed-100846802023-04-11 Pharmacological modulation of TSPO in microglia/macrophages and neurons in a chronic neurodegenerative model of prion disease Vicente-Rodríguez, Marta Mancuso, Renzo Peris-Yague, Alba Simmons, Camilla Gómez-Nicola, Diego Perry, V. Hugh Turkheimer, Federico Lovestone, Simon Parker, Christine A. Cash, Diana J Neuroinflammation Research Neuroinflammation is an important component of many neurodegenerative diseases, whether as a primary cause or a secondary outcome. For that reason, either as diagnostic tools or to monitor progression and/or pharmacological interventions, there is a need for robust biomarkers of neuroinflammation in the brain. Mitochondrial TSPO (18 kDa Translocator protein) is one of few available biomarkers of neuroinflammation for which there are clinically available PET imaging agents. In this study, we further characterised neuroinflammation in a mouse model of prion-induced chronic neurodegeneration (ME7) including a pharmacological intervention via a CSF1R inhibitor. This was achieved by autoradiographic binding of the second-generation TSPO tracer, [3H]PBR28, along with a more comprehensive examination of the cellular contributors to the TSPO signal changes by immunohistochemistry. We observed regional increases of TSPO in the ME7 mouse brains, particularly in the hippocampus, cortex and thalamus. This increased TSPO signal was detected in the cells of microglia/macrophage lineage as well as in astrocytes, endothelial cells and neurons. Importantly, we show that the selective CSF1R inhibitor, JNJ-40346527 (JNJ527), attenuated the disease-dependent increase in TSPO signal, particularly in the dentate gyrus of the hippocampus, where JNJ527 attenuated the number of Iba1+ microglia and neurons, but not GFAP+ astrocytes or endothelial cells. These findings suggest that [3H]PBR28 quantitative autoradiography in combination with immunohistochemistry are important translational tools for detecting and quantifying neuroinflammation, and its treatments, in neurodegenerative disease. Furthermore, we demonstrate that although TSPO overexpression in the ME7 brains was driven by various cell types, the therapeutic effect of the CSF1R inhibitor was primarily to modulate TSPO expression in microglia and neurons, which identifies an important route of biological action of this particular CSF1R inhibitor and provides an example of a cell-specific effect of this type of therapeutic agent on the neuroinflammatory process. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-023-02769-y. BioMed Central 2023-04-09 /pmc/articles/PMC10084680/ /pubmed/37032328 http://dx.doi.org/10.1186/s12974-023-02769-y Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Vicente-Rodríguez, Marta
Mancuso, Renzo
Peris-Yague, Alba
Simmons, Camilla
Gómez-Nicola, Diego
Perry, V. Hugh
Turkheimer, Federico
Lovestone, Simon
Parker, Christine A.
Cash, Diana
Pharmacological modulation of TSPO in microglia/macrophages and neurons in a chronic neurodegenerative model of prion disease
title Pharmacological modulation of TSPO in microglia/macrophages and neurons in a chronic neurodegenerative model of prion disease
title_full Pharmacological modulation of TSPO in microglia/macrophages and neurons in a chronic neurodegenerative model of prion disease
title_fullStr Pharmacological modulation of TSPO in microglia/macrophages and neurons in a chronic neurodegenerative model of prion disease
title_full_unstemmed Pharmacological modulation of TSPO in microglia/macrophages and neurons in a chronic neurodegenerative model of prion disease
title_short Pharmacological modulation of TSPO in microglia/macrophages and neurons in a chronic neurodegenerative model of prion disease
title_sort pharmacological modulation of tspo in microglia/macrophages and neurons in a chronic neurodegenerative model of prion disease
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10084680/
https://www.ncbi.nlm.nih.gov/pubmed/37032328
http://dx.doi.org/10.1186/s12974-023-02769-y
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