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

Renzo Mancuso ,Elena M Ribé ,Laura Winchester ,Declan N.c Jones ,Jimena Monzón‐Sandoval ,Amritpal Mudher ,Clara Theunis ,Nigel Austin ,Madeleine Cleal ,Diego Gomez‐Nicola ,Elena Pipi ,Caleb Webber ,Camilla Simmons ,Diana Cash ,Juliane Obst ,Karolien Grauwen ,Christine A Parker ,Eva Ruiz ,Alejo J Nevado ,Tom Jacobs ,Jill C Richardson ,Marta Vicente-Rodríguez ,Simon Lovestone ,Gemma Fryatt ,V Hugh Perry

doi: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.

Highlights

Alzheimer’s disease is the most common form of dementia affecting roughly 6–7% of the population aged 65, and up to 30% of people aged 85 and over (Hebert et al, 2003; Qiu et al, 2009)
Despite some evidence of neurodegeneration in brain areas such as perirhinal cortex (Yang et al, 2015) or superficial layers of the motor cortex (Hampton et al, 2010), we focused our attention on the spinal cord, as we believe it gives rise to readily assayed behavioural and cellular phenotype to dissect the contribution of microglial proliferation on tau-induced neurodegeneration
These results demonstrate that the blockade of microglial proliferation by JNJ-527 might lead to attenuation of tau pathology and results in a reduction of neuronal cell death in P301S mice

Summary

Introduction

Alzheimer’s disease is the most common form of dementia affecting roughly 6–7% of the population aged 65, and up to 30% of people aged 85 and over (Hebert et al, 2003; Qiu et al, 2009). The critical contribution of inflammation to Alzheimer’s disease pathogenesis has been further implicated by recent genome-wide association studies (GWAS), which highlight multiple immune-related genes in association with Alzheimer’s disease (Efthymiou and Goate, 2017), including the colony-stimulating factor 1 receptor (CSF1R) (Sassi et al, 2018). This evidence indicates that neuroinflammation and microglial activation are key drivers of Alzheimer’s disease pathology. CSF1R signalling mediates microglial proliferation and survival, and both upregulation of CSF1R and increased proliferation of microglia have been reported in post-mortem samples from patients with Alzheimer’s disease (Akiyama et al, 1994; Gomez-Nicola et al, 2013; Olmos-Alonso et al, 2016)

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