CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice.
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Authors
Mancuso, Renzo
Fryatt, Gemma
Cleal, Madeleine
Obst, Juliane
Pipi, Elena
Monzón-Sandoval, Jimena
Ribe, Elena
Winchester, Laura
Webber, Caleb
Nevado, Alejo
Jacobs, Tom
Austin, Nigel
Theunis, Clara
Grauwen, Karolien
Daniela Ruiz, Eva
Mudher, Amrit
Vicente-Rodriguez, Marta
Parker, Christine A
Simmons, Camilla
Cash, Diana
Richardson, Jill
NIMA Consortium,
Jones, Declan NC
Lovestone, Simon
Gómez-Nicola, Diego
Perry, V Hugh
Publication Date
2019-10-01Journal Title
Brain: a journal of neurology
ISSN
0006-8950
Publisher
Oxford University Press
Volume
142
Issue
10
Pages
3243-3264
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Mancuso, R., Fryatt, G., Cleal, M., Obst, J., Pipi, E., Monzón-Sandoval, J., Ribe, E., et al. (2019). CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice.. Brain: a journal of neurology, 142 (10), 3243-3264. https://doi.org/10.1093/brain/awz241
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.
Keywords
Alzheimer’s disease, CSF1R, microglia, neuroinflammation, tau
Sponsorship
Funded by a grant from the Wellcome Trust (Grant number: 104025/Z/14/Z), and by the NIHR Oxford Health Biomedical Research Centre.
Funder references
WELLCOME TRUST (104025/Z/14/Z)
Identifiers
External DOI: https://doi.org/10.1093/brain/awz241
This record's URL: https://www.repository.cam.ac.uk/handle/1810/299557