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

Mancuso, Renzo, Fryatt, Gemma, Cleal, Madeleine, Obst, Juliane, Pipi, Elena, Monzón-Sandoval, Jimena, Ribe, Elena, Winchester, Laura, Webber, Caleb ORCID: https://orcid.org/0000-0001-8063-7674, Nevado, Alejo, Jacobs, Tom, Austin, Nigel, Theunis, Clara, Grauwen, Karolien, Ruiz, Eva Daniela, Mudher, Amrit, Vicente-Rodriguez, Marta, Parker, Christine A., Simmons, Camilla, Cash, Diana, Richardson, Jill, Bullmore, Edward T., Bhatti, Junaid, Chamberlain, Samuel J., Correia, Marta M., Crofts, Anna L., Dickinson, Amber, Foster, Andrew C., Kitzbichler, Manfred G., Knight, Clare, Lynall, Mary-Ellen, Maurice, Christina, O'Donnell, Ciara, Pointon, Linda J., Hyslop, Peter St. George, Turner, Lorinda, Vertes, Petra, Widmer, Barry, Williams, Guy B., Morgan, B. Paul ORCID: https://orcid.org/0000-0003-4075-7676, Leckey, Claire A., Morgan, Angharad R. ORCID: https://orcid.org/0000-0003-4075-7676, O'Hagan, Caroline, Touchard, Samuel, Cavanagh, Jonathan, Deith, Catherine, Farmer, Scott, McClean, John, McColl, Alison, McPherson, Andrew, Scouller, Paul, Sutherland, Murray, Boddeke, H. W. G. M. (Erik), Richardson, Jill C., Khan, Shahid, Murphy, Phil, Parker, Christine A., Patel, Jai, Jones, Declan, de Boer, Peter, Kemp, John, Drevets, Wayne C., Nye, Jeffrey S., Wittenberg, Gayle, Isaac, John, Bhattacharya, Anindya, Carruthers, Nick, Kolb, Hartmuth, Pariante, Carmine M., Turkheimer, Federico, Barker, Gareth J., Byrom, Heidi, Cash, Diana, Cattaneo, Annamaria, Gee, Antony, Hastings, Caitlin, Mariani, Nicole, McLaughlin, Anna, Mondelli, Valeria, Nettis, Maria, Nikkheslat, Naghmeh, Randall, Karen, Sheridan, Hannah, Simmons, Camilla, Singh, Nisha, VAn Loo, Victoria, Vicente-Rodriguez, Marta, Wood, Tobias C, Worrell, Courtney, Zajkowska, Zuzanna, Plath, Niels, Egebjerg, Jan, Eriksson, Hans, Gastambide, Francois, Adams, Karen Husted, Jeggo, Ross, Thomsen, Christian, Pederson, Jan Torleif, Campbell, Brian, Möller, Thomas, Nelson, Bob, Zorn, Stevin, O'Connor, Jason, Attenburrow, Mary Jane, Baird, Alison, Benjamin, Jithen, Clare, Stuart, Cowen, Philip, Huang, I-Shu (Dante), Hurley, Samuel, Jones, Helen, Lovestone, Simon, Mada, Francisca, Nevado-Holgado, Alejo, Oladejo, Akintayo, Ribe, Elena, Smith, Katy, Vyas, Anviti, Hughes, Zoe, Balice-Gordon, Rita, Duerr, James, Piro, Justin R, Sporn, Jonathan, Perry (PI), V Hugh, Cleal, Madeleine, Fryatt, Gemma, Gomez-Nicola, Diego, Mancuso, Renzo, Reynolds, Richard, Harrison, Neil A. ORCID: https://orcid.org/0000-0002-9584-3769, Cercignani, Mara ORCID: https://orcid.org/0000-0002-4550-2456, Clarke, Charlotte L, Hoskins, Elizabeth, Kohn, Charmaine, Murray, Rosemary, Wilcock, Lauren, Wlazly, Dominika, Mount, Howard, Jones, Declan N. C., Lovestone, Simon, Gomez-Nicola, Diego and Perry, V. Hugh 2019. CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice. Brain 142 (10) , pp. 3243-3264. 10.1093/brain/awz241

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Cardiff University Brain Research Imaging Centre (CUBRIC) Medicine Psychology
Additional Information:	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.
Publisher:	Oxford University Press
ISSN:	0006-8950
Date of First Compliant Deposit:	28 August 2019
Date of Acceptance:	14 June 2019
Last Modified:	05 May 2023 12:56
URI:	https://orca.cardiff.ac.uk/id/eprint/125159

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