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CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice

CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice
CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice
Neuroinflammation and microglial activation are significant processes in Alzheimer’s disease pathology. Recent genome-wide association studies have highlighted multiple immune-related genes in association with Alzheimer’s disease, and experimental data have demonstrated microglial proliferation as a significant component of the neuropathology. In this study, we tested the efficacy of the selective CSF1R inhibitor JNJ-40346527 (JNJ-527) in the P301S mouse tauopathy model. We first demonstrated the anti-proliferative effects of JNJ-527 on microglia in the ME7 prion model, and its impact on the inflammatory profile, and provided potential CNS biomarkers for clinical investigation with the compound, including pharmacokinetic/pharmacodynamics and efficacy assessment by TSPO autoradiography and CSF proteomics. Then, we showed for the first time that blockade of microglial proliferation and modification of microglial phenotype leads to an attenuation of tau-induced neurodegeneration and results in functional improvement in P301S mice. Overall, this work strongly supports the potential for inhibition of CSF1R as a target for the treatment of Alzheimer’s disease and other tau-mediated neurodegenerative diseases.
0006-8950
3243-3264
Mancuso, Renzo
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Fryatt, Gemma
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Cleal, Madeleine E.
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Obst, Juliane
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Pipi, Eleni
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Monzon-Sandoval, Jimena
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Ribe, Elena
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Winchester, Laura
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Webber, Caleb
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Nevado, Alejo
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Jacobs, Tom
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Austin, Nigel
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Theunis, Clara
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Grauwen, Karolien
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Ruiz Ortega, Eva, Daniela
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Mudher, Amritpal
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Vicente-Rodriquez, Marta
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Parker, Christine
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Simmons, Camilla
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Cash, Diana
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Richardson, Jill
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Jones, Declan
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Lovestone, Simon
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Gomez-Nicola, Diego
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Perry, V. Hugh
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NIMA Consortium
Mancuso, Renzo
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Fryatt, Gemma
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Cleal, Madeleine E.
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Obst, Juliane
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Pipi, Eleni
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Monzon-Sandoval, Jimena
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Ribe, Elena
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Winchester, Laura
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Webber, Caleb
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Nevado, Alejo
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Jacobs, Tom
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Austin, Nigel
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Theunis, Clara
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Grauwen, Karolien
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Ruiz Ortega, Eva, Daniela
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Mudher, Amritpal
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Vicente-Rodriquez, Marta
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Parker, Christine
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Simmons, Camilla
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Cash, Diana
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Richardson, Jill
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Jones, Declan
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Lovestone, Simon
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Gomez-Nicola, Diego
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Perry, V. Hugh
8f29d36a-8e1f-4082-8700-09483bbaeae4

Mancuso, Renzo, Fryatt, Gemma, Cleal, Madeleine E., Obst, Juliane, Pipi, Eleni, Monzon-Sandoval, Jimena, Ribe, Elena, Winchester, Laura, Webber, Caleb, Nevado, Alejo, Jacobs, Tom, Austin, Nigel, Theunis, Clara, Grauwen, Karolien, Ruiz Ortega, Eva, Daniela, Mudher, Amritpal, Vicente-Rodriquez, Marta, Parker, Christine, Simmons, Camilla, Cash, Diana, Richardson, Jill, Jones, Declan, Lovestone, Simon, Gomez-Nicola, Diego and Perry, V. Hugh , NIMA Consortium (2019) CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice. Brain, 142 (10), 3243-3264. (doi:10.1093/brain/awz241).

Record type: Article

Abstract

Neuroinflammation and microglial activation are significant processes in Alzheimer’s disease pathology. Recent genome-wide association studies have highlighted multiple immune-related genes in association with Alzheimer’s disease, and experimental data have demonstrated microglial proliferation as a significant component of the neuropathology. In this study, we tested the efficacy of the selective CSF1R inhibitor JNJ-40346527 (JNJ-527) in the P301S mouse tauopathy model. We first demonstrated the anti-proliferative effects of JNJ-527 on microglia in the ME7 prion model, and its impact on the inflammatory profile, and provided potential CNS biomarkers for clinical investigation with the compound, including pharmacokinetic/pharmacodynamics and efficacy assessment by TSPO autoradiography and CSF proteomics. Then, we showed for the first time that blockade of microglial proliferation and modification of microglial phenotype leads to an attenuation of tau-induced neurodegeneration and results in functional improvement in P301S mice. Overall, this work strongly supports the potential for inhibition of CSF1R as a target for the treatment of Alzheimer’s disease and other tau-mediated neurodegenerative diseases.

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Mancuso et al Brain final - Accepted Manuscript
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More information

Accepted/In Press date: 14 June 2019
e-pub ahead of print date: 26 August 2019
Published date: October 2019

Identifiers

Local EPrints ID: 433565
URI: http://eprints.soton.ac.uk/id/eprint/433565
ISSN: 0006-8950
PURE UUID: e16c04cc-fca5-4539-a3ba-8fe4dd297935
ORCID for Diego Gomez-Nicola: ORCID iD orcid.org/0000-0002-5316-2682

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Date deposited: 27 Aug 2019 16:30
Last modified: 07 Oct 2020 05:25

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