CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice
Renzo Mancuso1, Gemma Fryatt1, Madeleine Cleal1
1Biological Sciences, University of Southampton, Southampton General Hospital, Southampton, UK.
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.
Insights
Inhibiting colony-stimulating factor 1 receptor (CSF1R) reduces microglial proliferation and neuroinflammation, offering a potential treatment for Alzheimer's disease and other tauopathies.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Neuroinflammation and microglial activation are key in Alzheimer's disease (AD) pathology.
- Genome-wide association studies link immune genes to AD risk.
- Microglial proliferation is a significant neuropathological feature in AD.
Purpose of the Study:
- To evaluate the efficacy of the selective CSF1R inhibitor JNJ-40346527 (JNJ-527) in a mouse model of tauopathy.
- To assess the compound's effects on microglial proliferation, neuroinflammation, and neurodegeneration.
- To identify potential central nervous system (CNS) biomarkers for clinical use.
Main Methods:
- Testing JNJ-527's anti-proliferative effects on microglia in the ME7 prion model.
- Assessing JNJ-527's impact on the inflammatory profile and CNS biomarkers.
- Evaluating efficacy using TSPO autoradiography and cerebrospinal fluid (CSF) proteomics in P301S mice.
- Investigating the blockade of microglial proliferation and phenotype modification.
Main Results:
- JNJ-527 demonstrated anti-proliferative effects on microglia and modulated the inflammatory profile.
- Pharmacokinetic/pharmacodynamic and biomarker assessments were performed.
- Blockade of microglial proliferation attenuated tau-induced neurodegeneration in P301S mice.
- Functional improvement was observed in P301S mice treated with JNJ-527.
Conclusions:
- Inhibition of CSF1R effectively reduces microglial proliferation and neuroinflammation.
- Targeting CSF1R shows promise for treating Alzheimer's disease and tau-mediated neurodegenerative diseases.
- JNJ-527 represents a potential therapeutic strategy for these conditions.
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