CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice
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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.
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[3H]PBR28 binding was significantly increased in the cortex, hippocampus and thalamus of ME7 vs. NBH mice.
“[3H]PBR28 binding was significantly increased in the cortex, hippocampus and thalamus of ME7 vs. NBH mice, in line with previous findings [33, 37].”
From Pharmacological modulation of TSPO in microglia/macrophages and neurons in a chronic neurodegenerative model of prion disease (2023) · cites this paper as [33]
The Results section reports significantly increased TSPO signal in the hippocampus, somatosensory cortex and thalamus of ME7 versus NBH mice. However, the Methods section (TSPO autoradiography) identifies the ligand as [3H]PK11195, not [3H]PBR28. The regional finding is supported, but the claim names the wrong tracer. (LLM, conf=0.90)
Experimental — accuracy not yet measuredMicroglia are the principal driving force of neurodegeneration and tau pathogenesis in tauopathy mouse models.
“We and others subsequently identified microglia as the principal driving force of neurodegeneration and tau pathogenesis in tauopathy mouse models (Mancuso et al., 2019; Shi et al., 2019).”
From Overexpressing low‐density lipoprotein receptor reduces tau‐associated neurodegeneration in relation to apoE‐linked mechanisms (2021) · cites this paper as Mancuso et al., 2019
The Discussion reports that inhibiting microglial proliferation in P301S mice prevented neurodegeneration and potentially slowed tau aggregation. It describes activated microglia as deleterious, but does not establish them as the principal driving force of either process across tauopathy mouse models; it explicitly notes uncertainty about whether their effect on tau pathology is predominant. The indexed passages provide section labels but no page numbers. (LLM, conf=0.86)
Experimental — accuracy not yet measuredStudies using transgenic P301STau mice report that microglial depletion reduced neurodegeneration and the accumulation of phosphorylated tau.
“In line with our findings, studies using transgenic P301STau mice report that microglial depletion reduced neurodegeneration and the accumulation of phosphorylated tau (Johnson et al., 2023; Mancuso et al., 2019; Shi et al., 2019).”
From A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation (2023) · cites this paper as Mancuso et al., 2019
The selective CSF1R inhibitor JNJ527 significantly blocked microglial proliferation in the ME7 mouse model of prion disease, as detected by ex vivo autoradiography with [3H]PK11195.
“We previously demonstrated that the selective CSF1R inhibitor JNJ527 significantly blocked microglial proliferation in the ME7 mouse model of prion disease, and this has been detected by ex vivo autoradiography with the first generation TSPO ligand, [3H]PK11195 [33].”
From Pharmacological modulation of TSPO in microglia/macrophages and neurons in a chronic neurodegenerative model of prion disease (2023) · cites this paper as [33]
In the ME7 mouse, the selective CSF1R inhibitor JNJ527 significantly blocks microglial proliferation, as shown by reduced [3H]PK11195 binding on autoradiography.
“Using the ME7 mouse, we previously corroborated the ability of the selective colony stimulating factor receptor 1 (CSF1R) inhibitor, JNJ-40346527 (JNJ527), to significantly block microglial proliferation. This was demonstrated by the reduced binding of the first generation TSPO tracer, [3H]PK11195, using autoradiography [33].”
From Pharmacological modulation of TSPO in microglia/macrophages and neurons in a chronic neurodegenerative model of prion disease (2023) · cites this paper as [33]
The demonstration of increased TSPO in experimental prion disease aligns with earlier findings using the first generation TSPO radiotracer [3H]PK11195.
“This demonstration of increased TSPO in experimental prion disease aligns with ours and others’ earlier findings using the first generation TSPO radiotracer [3H]PK11195 [33, 37].”
From Pharmacological modulation of TSPO in microglia/macrophages and neurons in a chronic neurodegenerative model of prion disease (2023) · cites this paper as [33]
JNJ527 attenuates microglia proliferation in models of neurodegeneration.
“CSF1R inhibitor JNJ527 is a tool compound that was previously shown to attenuate microglia proliferation and provide therapeutic action in models of neurodegeneration including ME7 prion mice and in the P301S mouse tauopathy model [33].”
From Pharmacological modulation of TSPO in microglia/macrophages and neurons in a chronic neurodegenerative model of prion disease (2023) · cites this paper as [33]
JNJ527 provides therapeutic action in models of neurodegeneration including ME7 prion mice and P301S tauopathy mice.
“CSF1R inhibitor JNJ527 is a tool compound that was previously shown to attenuate microglia proliferation and provide therapeutic action in models of neurodegeneration including ME7 prion mice and in the P301S mouse tauopathy model [33].”
From Pharmacological modulation of TSPO in microglia/macrophages and neurons in a chronic neurodegenerative model of prion disease (2023) · cites this paper as [33]
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Emerging diagnostics and therapeutics for Alzheimer disease
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Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy
Wang, C., Fan, L., Khawaja, R. R., Liu, B., Zhan, L., Kodama, L., Chin, M., Li, Y., Le, D., Zhou, Y., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-29552-6 · Cited by 333 · see citing works
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Hu, Y., Fryatt, G. L., Ghorbani, M., Obst, J., Menassa, D. A., Martin-Estebane, M., Muntslag, T. A. O., Olmos-Alonso, A., Guerrero-Carrasco, M., Thomas, D., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109228 · Cited by 298 · see citing works
Self-citationTauopathies: new perspectives and challenges
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Emerging roles of innate and adaptive immunity in Alzheimer’s disease
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Novel Alzheimer risk genes determine the microglia response to amyloid-β but not to TAU pathology
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Activated microglia mitigate Aβ-associated tau seeding and spreading
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A multi-pronged human microglia response to Alzheimer’s disease Aβ pathology
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Disease-Modifying Therapies for Alzheimer’s Disease: More Questions than Answers
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Gut microbiota–driven brain Aβ amyloidosis in mice requires microglia
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<i>APOE</i> ε4 associates with microglial activation independently of Aβ plaques and tau tangles
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The <scp>NLRP3</scp> inflammasome modulates tau pathology and neurodegeneration in a tauopathy model
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Self-citationA novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation
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“In line with our findings, studies using transgenic P301STau mice report that microglial depletion reduced neurodegeneration and the accumulation of phosphorylated tau (Johnson et al., 2023; Mancuso et al., 2019; Shi et al., 2019).”
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“This was demonstrated by the reduced binding of the first generation TSPO tracer, [3H]PK11195, using autoradiography [33].”
BackgroundMethodResultInfluentialSelf-citation
- Authors
- Mancuso, R., Fryatt, G., Cleal, M., Obst, J., Pipi, E., Monzón-Sandoval, J., Ribe, E., Winchester, L., Webber, C., Nevado, A., Jacobs, T., Austin, N., Theunis, C., Grauwen, K., Daniela Ruiz, E., Mudher, A., Vicente-Rodriguez, M., Parker, C. A., Simmons, C., Cash, D., Richardson, J., NIMA Consortium, Bullmore, E. T., Bhatti, J., Chamberlain, S. J., Correia, M. M., Crofts, A. L., Dickinson, A., Foster, A. C., Kitzbichler, M. G., Knight, C., Lynall, M.-E., Maurice, C., O'Donnell, C., Pointon, L. J., Hyslop, P. S. G., Turner, L., Vertes, P., Widmer, B., Williams, G. B., Morgan, B. P., Leckey, C. A., Morgan, A. R., O'Hagan, C., Touchard, S., Cavanagh, J., Deith, C., Farmer, S., McClean, J., McColl, A., McPherson, A., Scouller, P., Sutherland, M., Boddeke, H. W. G. M. (., Richardson, J. C., Khan, S., Murphy, P., Parker, C. A., Patel, J., Jones, D., de Boer, P., Kemp, J., Drevets, W. C., Nye, J. S., Wittenberg, G., Isaac, J., Bhattacharya, A., Carruthers, N., Kolb, H., Pariante, C. M., Turkheimer, F., Barker, G. J., Byrom, H., Cash, D., Cattaneo, A., Gee, A., Hastings, C., Mariani, N., McLaughlin, A., Mondelli, V., Nettis, M., Nikkheslat, N., Randall, K., Sheridan, H., Simmons, C., Singh, N., Loo, V. V., Vicente-Rodriguez, M., Wood, T. C., Worrell, C., Zajkowska, Z., Plath, N., Egebjerg, J., Eriksson, H., Gastambide, F., Adams, K. H., Jeggo, R., Thomsen, C., Pederson, J. T., Campbell, B., Möller, T., Nelson, B., Zorn, S., O'Connor, J., Attenburrow, M. J., Baird, A., Benjamin, J., Clare, S., Cowen, P., Huang, I.-S. (., Hurley, S., Jones, H., Lovestone, S., Mada, F., Nevado-Holgado, A., Oladejo, A., Ribe, E., Smith, K., Vyas, A., Hughes, Z., Balice-Gordon, R., Duerr, J., Piro, J. R., Sporn, J., Hugh Perry (PI, V, Cleal, M., Fryatt, G., Gomez-Nicola, D., Mancuso, R., Reynolds, R., Harrison, N. A., Cercignani, M., Clarke, C. L., Hoskins, E., Kohn, C., Murray, R., Wilcock, L., Wlazly, D., Mount, H., Jones, D. N. C., Lovestone, S., Gómez-Nicola, D., & Perry, V. H.
- Affiliations
- Southampton General Hospital (GB)
- Department of Physiology Anatomy and Genetics, University of Oxford, Sherrington Building, Parks Road, Oxford OX1 3PT, UK
- University of Oxford (GB)
- Janssen (Belgium) (BE)
- Biological Sciences, University of Southampton, Southampton General Hospital, Southampton, UK
- Neurosciences Therapeutic Area, GlaxoSmithKline R&D, Stevenage, UK
- Janssen (United Kingdom) (GB)
- Janssen Neuroscience External Innovation, Johnson and Johnson Innovation Centre, One Chapel Place, London, W1G 0BG, UK
- ORCID
- Obst, Juliane
- Pipi, Elena
- Winchester, Laura
- Webber, Caleb
- Theunis, Clara
- Bullmore, Edward T
- Correia, Marta M
- Kitzbichler, Manfred G
- Lynall, Mary-Ellen
- Pointon, Linda J
- Turner, Lorinda
- Williams, Guy B
- Morgan, B Paul
- Leckey, Claire A
- Cavanagh, Jonathan
- McColl, Alison
- Boddeke, H W G M (Erik)
- Drevets, Wayne C
- Nye, Jeffrey S
- Wittenberg, Gayle
- Kolb, Hartmuth
- Pariante, Carmine M
- Turkheimer, Federico
- Barker, Gareth J
- Cattaneo, Annamaria
- Gee, Antony
- Mariani, Nicole
- McLaughlin, Anna
- Mondelli, Valeria
- Nettis, Maria
- Nikkheslat, Naghmeh
- Randall, Karen
- Singh, Nisha
- Wood, Tobias C
- Worrell, Courtney
- Zajkowska, Zuzanna
- Plath, Niels
- Eriksson, Hans
- Möller, Thomas
- Attenburrow, Mary Jane
- Clare, Stuart
- Cowen, Philip
- Hurley, Samuel
- Piro, Justin R
- Reynolds, Richard
- Harrison, Neil A
- Cercignani, Mara
- Kohn, Charmaine
- Mount, Howard
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2019-08-26
- Volume
- 142
- Issue
- 10
- Pages
- 3243-3264
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC6794948
- OpenAlex
- W2971030533
- Cited by
- 235
- References
- 71
- Citations by year
- 2026: 15 · 2025: 30 · 2024: 38 · 2023: 34 · 2022: 54 · 2021: 40 · 2020: 22 · 2019: 2
- FWCI
- 13.10
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Brain (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, cc-by)
- ePrints Soton (University of Southampton) (submittedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Research Portal (King's College London) (submittedVersion, cc-by)
- CEU Repositorio Institucional (Fundación Universitaria San Pablo CEU) (submittedVersion, cc-by-nc-nd)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- Wellcome Trust (104025/Z/14/Z)
- NIHR Oxford Health Biomedical Research Centre
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- CSF1R inhibitor, microglial proliferation, neuroinflammation, Alzheimer's disease, microglial phenotype, CSF proteomics, pharmacokinetics/pharmacodynamics, neurodegenerative diseases
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Humans, Imidazoles, Mice, Transgenic, Pyridines, Neuroimmunomodulation, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, tau Proteins, Microglia, Receptors, GABA, Neurodegenerative Diseases, Tauopathies, Cell Proliferation, Mice, Genome-Wide Association Study, Neurogenesis
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