Inflammasome signaling is dispensable for ß-amyloid-induced neuropathology in preclinical models of Alzheimer's disease.

Autor:	Srinivasan S; VIB Center for Inflammation Research, Ghent, Belgium.; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium., Kancheva D; Brain and Systems Immunology Lab, Brussels Center for Immunology, Vrije Universiteit Brussel, Brussels, Belgium., De Ren S; Neuroscience Therapeutic Area, Janssen Research and Development, Beerse, Belgium., Saito T; Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Saitama, Japan.; Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.; Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, Japan., Jans M; VIB Center for Inflammation Research, Ghent, Belgium.; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium., Boone F; VIB Center for Inflammation Research, Ghent, Belgium.; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium., Vandendriessche C; VIB Center for Inflammation Research, Ghent, Belgium.; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium., Paesmans I; Neuroscience Therapeutic Area, Janssen Research and Development, Beerse, Belgium., Maurin H; Neuroscience Therapeutic Area, Janssen Research and Development, Beerse, Belgium., Vandenbroucke RE; VIB Center for Inflammation Research, Ghent, Belgium.; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium., Hoste E; VIB Center for Inflammation Research, Ghent, Belgium.; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium., Voet S; VIB Center for Inflammation Research, Ghent, Belgium.; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium., Scheyltjens I; Brain and Systems Immunology Lab, Brussels Center for Immunology, Vrije Universiteit Brussel, Brussels, Belgium., Pavie B; VIB Center for Inflammation Research, Ghent, Belgium.; VIB Bioimaging Core, Ghent, Belgium., Lippens S; VIB Center for Inflammation Research, Ghent, Belgium.; VIB Bioimaging Core, Ghent, Belgium., Schwabenland M; Institute of Neuropathology Medical Center, University of Freiburg, Freiburg, Germany., Prinz M; Institute of Neuropathology Medical Center, University of Freiburg, Freiburg, Germany.; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany.; Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg, Freiburg, Germany., Saido T; Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Saitama, Japan., Bottelbergs A; Neuroscience Therapeutic Area, Janssen Research and Development, Beerse, Belgium., Movahedi K; Brain and Systems Immunology Lab, Brussels Center for Immunology, Vrije Universiteit Brussel, Brussels, Belgium., Lamkanfi M; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium., van Loo G; VIB Center for Inflammation Research, Ghent, Belgium.; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2024 Jan 29; Vol. 15, pp. 1323409. Date of Electronic Publication: 2024 Jan 29 (Print Publication: 2024).
DOI:	10.3389/fimmu.2024.1323409
Abstrakt:	Background: Alzheimer's disease (AD) is the most common neurodegenerative disorder affecting memory and cognition. The disease is accompanied by an abnormal deposition of ß-amyloid plaques in the brain that contributes to neurodegeneration and is known to induce glial inflammation. Studies in the APP/PS1 mouse model of ß-amyloid-induced neuropathology have suggested a role for inflammasome activation in ß-amyloid-induced neuroinflammation and neuropathology. Methods: Here, we evaluated the in vivo role of microglia-selective and full body inflammasome signalling in several mouse models of ß-amyloid-induced AD neuropathology. Results: Microglia-specific deletion of the inflammasome regulator A20 and inflammasome effector protease caspase-1 in the App NL-G-F and APP/PS1 models failed to identify a prominent role for microglial inflammasome signalling in ß-amyloid-induced neuropathology. Moreover, global inflammasome inactivation through respectively full body deletion of caspases 1 and 11 in App NL-G-F mice and Nlrp3 deletion in APP/PS1 mice also failed to modulate amyloid pathology and disease progression. In agreement, single-cell RNA sequencing did not reveal an important role for Nlrp3 signalling in driving microglial activation and the transition into disease-associated states, both during homeostasis and upon amyloid pathology. Conclusion: Collectively, these results question a generalizable role for inflammasome activation in preclinical amyloid-only models of neuroinflammation. Competing Interests: SD, IP, HM, and AB are employed by Janssen Pharmaceutica NV. ML serves as a consultant for Ventyx Biosciences and Novo Nordisk outside of the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2024 Srinivasan, Kancheva, De Ren, Saito, Jans, Boone, Vandendriessche, Paesmans, Maurin, Vandenbroucke, Hoste, Voet, Scheyltjens, Pavie, Lippens, Schwabenland, Prinz, Saido, Bottelbergs, Movahedi, Lamkanfi and van Loo.)
Databáze:	MEDLINE
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