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

Renzo Mancuso; Gemma Fryatt; Madeleine Cleal; Juliane Obst; Elena Pipi; Jimena Monzon-Sandoval; Elena M. 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 C. Richardson; Declan Jones; Simon Lovestone; Diego Gomez-Nicola; V Hugh Perry

doi:10.1093/brain/awz241

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

Renzo Mancuso, Gemma Fryatt, Madeleine Cleal, Juliane Obst, Elena Pipi, Jimena Monzon-Sandoval, Elena M. 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 CashJill C. Richardson, Declan Jones, Simon Lovestone, Diego Gomez-Nicola, V Hugh Perry

Neuroimaging

Research output: Contribution to journal › Article › peer-review

151 Citations (Scopus)

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.

Original language	English
Pages (from-to)	3243-3264
Number of pages	22
Journal	Brain : a journal of neurology
Volume	142
Issue number	10
DOIs	https://doi.org/10.1093/brain/awz241
Publication status	Published - 1 Oct 2019

Keywords

Alzheimer’s disease
CSF1R
microglia
neuroinflammation
tau

Access to Document

10.1093/brain/awz241Licence: CC BY

Cite this

Mancuso, R., Fryatt, G., Cleal, M., Obst, J., Pipi, E., Monzon-Sandoval, J., Ribe, E. M., Winchester, L., Webber, C., Nevado, A., Jacobs, T., Austin, N., Theunis, C., Grauwen, K., Ruiz, E. D., Mudher, A., Vicente Rodriguez, M., Parker, C. A., Simmons, C., ... Perry, V. H. (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

@article{afdef84cb1ae45e68f571664a39e5950,

title = "CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice",

abstract = "Neuroinflammation and microglial activation are significant processes in Alzheimer{\textquoteright}s disease pathology. Recent genome-wide association studies have highlighted multiple immune-related genes in association with Alzheimer{\textquoteright}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{\textquoteright}s disease and other tau-mediated neurodegenerative diseases.",

keywords = "Alzheimer{\textquoteright}s disease, CSF1R, microglia, neuroinflammation, tau",

author = "Renzo Mancuso and Gemma Fryatt and Madeleine Cleal and Juliane Obst and Elena Pipi and Jimena Monzon-Sandoval and Ribe, {Elena M.} and Laura Winchester and Caleb Webber and Alejo Nevado and Tom Jacobs and Nigel Austin and Clara Theunis and Karolien Grauwen and Ruiz, {Eva Daniela} and Amrit Mudher and {Vicente Rodriguez}, Marta and Parker, {Christine A} and Camilla Simmons and Diana Cash and Richardson, {Jill C.} and Declan Jones and Simon Lovestone and Diego Gomez-Nicola and Perry, {V Hugh}",

year = "2019",

month = oct,

day = "1",

doi = "10.1093/brain/awz241",

language = "English",

volume = "142",

pages = "3243--3264",

journal = "Brain : a journal of neurology",

issn = "0006-8950",

publisher = "Oxford University Press (OUP)",

number = "10",

}

Mancuso, R, Fryatt, G, Cleal, M, Obst, J, Pipi, E, Monzon-Sandoval, J, Ribe, EM, Winchester, L, Webber, C, Nevado, A, Jacobs, T, Austin, N, Theunis, C, Grauwen, K, Ruiz, ED, Mudher, A, Vicente Rodriguez, M, Parker, CA, Simmons, C , Cash, D, Richardson, JC, Jones, D, Lovestone, S, Gomez-Nicola, D & Perry, VH 2019, 'CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice', Brain : a journal of neurology, vol. 142, no. 10, pp. 3243-3264. https://doi.org/10.1093/brain/awz241

TY - JOUR

T1 - CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice

AU - Mancuso, Renzo

AU - Fryatt, Gemma

AU - Cleal, Madeleine

AU - Obst, Juliane

AU - Pipi, Elena

AU - Monzon-Sandoval, Jimena

AU - Ribe, Elena M.

AU - Winchester, Laura

AU - Webber, Caleb

AU - Nevado, Alejo

AU - Jacobs, Tom

AU - Austin, Nigel

AU - Theunis, Clara

AU - Grauwen, Karolien

AU - Ruiz, Eva Daniela

AU - Mudher, Amrit

AU - Vicente Rodriguez, Marta

AU - Parker, Christine A

AU - Simmons, Camilla

AU - Cash, Diana

AU - Richardson, Jill C.

AU - Jones, Declan

AU - Lovestone, Simon

AU - Gomez-Nicola, Diego

AU - Perry, V Hugh

PY - 2019/10/1

Y1 - 2019/10/1

N2 - 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.

AB - 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.

KW - Alzheimer’s disease

KW - CSF1R

KW - microglia

KW - neuroinflammation

KW - tau

UR - http://www.scopus.com/inward/record.url?scp=85072716789&partnerID=8YFLogxK

U2 - 10.1093/brain/awz241

DO - 10.1093/brain/awz241

M3 - Article

SN - 0006-8950

VL - 142

SP - 3243

EP - 3264

JO - Brain : a journal of neurology

JF - Brain : a journal of neurology

IS - 10

ER -

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

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this