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 CashJill Richardson, Declan N.C. Jones, Simon Lovestone, Diego Gómez-Nicola, V. Hugh Perry, Edward T. Bullmore, Junaid Bhatti, Samuel J. Chamberlain, Marta M. Correia, Anna L. Crofts, Amber Dickinson, Andrew C. Foster, Manfred G. Kitzbichler, Clare Knight, Mary Ellen Lynall, Christina Maurice, Ciara O'Donnell, Linda J. Pointon, Peter St George Hyslop, Lorinda Turner, Petra Vertes, Barry Widmer, Guy B. Williams, B. Paul Morgan, Claire A. Leckey, Angharad R. Morgan, Caroline O'Hagan, Samuel Touchard, Jonathan Cavanagh, Catherine Deith, Scott Farmer, John McClean, Alison McColl, Andrew McPherson, Paul Scouller, Murray Sutherland, H. W.G.M. Boddeke, Jill C. Richardson, Shahid Khan, Phil Murphy, Christine A. Parker, Jai Patel, Declan Jones, Peter De Boer, John Kemp, Wayne C. Drevets, Jeffrey S. Nye, Gayle Wittenberg, John Isaac, Anindya Bhattacharya, Nick Carruthers, Hartmuth Kolb, Carmine M. Pariante, Federico Turkheimer, Gareth J. Barker, Heidi Byrom, Diana Cash, Annamaria Cattaneo, Antony Gee, Caitlin Hastings, Nicole Mariani, Anna McLaughlin, Valeria Mondelli, Maria Nettis, Naghmeh Nikkheslat, Karen Randall, Hannah Sheridan, Camilla Simmons, Nisha Singh, Victoria Van Loo, Marta Vicente-Rodriguez, Tobias C. Wood, Courtney Worrell, Zuzanna Zajkowska, Niels Plath, Jan Egebjerg, Hans Eriksson, Francois Gastambide, Karen Husted Adams, Ross Jeggo, Christian Thomsen, Jan Torleif Pederson, Brian Campbell, Thomas Möller, Bob Nelson, Stevin Zorn, Jason O'Connor, Mary Jane Attenburrow, Alison Baird, Jithen Benjamin, Stuart Clare, Philip Cowen, I. Shu Huang, Samuel Hurley, Helen Jones, Francisca Mada, Alejo Nevado-Holgado, Akintayo Oladejo, Elena Ribe, Katy Smith, Anviti Vyas, Zoe Hughes, Rita Balice-Gordon, James Duerr, Justin R. Piro, Jonathan Sporn, V. Hugh Perry, Madeleine Cleal, Gemma Fryatt, Diego Gomez-Nicola, Renzo Mancuso, Richard Reynolds, Neil A. Harrison, Mara Cercignani, Charlotte L. Clarke, Elizabeth Hoskins, Charmaine Kohn, Rosemary Murray, Lauren Wilcock, Dominika Wlazly, Howard Mount

Research output: Contribution to journalArticlepeer-review

88 Scopus citations

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 languageEnglish (US)
Pages (from-to)3243-3264
Number of pages22
JournalBrain
Volume142
Issue number10
DOIs
StatePublished - Oct 1 2019

Keywords

  • Alzheimer's disease
  • CSF1R
  • Microglia
  • Neuroinflammation
  • Tau

ASJC Scopus subject areas

  • Medicine(all)

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