CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice
Renzo Mancuso, Gemma Fryatt, Madeleine Cleal, Juliane Obst, Elena Pipi,Jimena Monzón-Sandoval, Elena Ribe, Laura Winchester,Caleb Webber, Alejo Nevado, Tom Jacobs, Nigel Austin, Clara Theunis, Karolien Grauwen, Eva Daniela Ruiz, Amrit Mudher, Marta Vicente-Rodriguez, Christine A Parker,Camilla Simmons, Diana Cash, Jill Richardson,NIMA Consortium, Declan N C Jones,Simon Lovestone, Diego Gómez-Nicola, V Hugh Perry. CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice. Brain, awz241
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.
Published online at: https://doi.org/10.1093/brain/awz241 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
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