Abstract
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 AppNL-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 AppNL-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.
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 AppNL-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 AppNL-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.
Original language | English |
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Article number | 1323409 |
Number of pages | 20 |
Journal | Front Immunol. |
Volume | 15 |
DOIs | |
Publication status | Published - 29 Jan 2024 |
Bibliographical note
Funding Information:The author(s) declare financial support was received for the research, authorship, and/or publication of this article. SS was supported by an FWO PhD fellowship. Research in the van Loo lab was also supported by VIB and by research grants from the FWO (G090322N, G026520N, G012618N, EOS-G0H2522N-40007505), the “Geneeskundige Stichting Koningin Elisabeth” (GSKE), the Charcot Foundation, and the “Concerted Research Actions” (GOA) of Ghent University (BOF23/GOA/001). Research in the Lamkanfi lab is supported by Ghent University (BOF23/GOA/001), and by research grants from the FWO (GOI5722N, G017121N, G014221N) and European Research Council (ERC-2022-PoC 101101075). Research in the Saito lab was supported by grants-in-aid for Scientific Research (20H03564) from MEXT, AMED (JP21gm1210010s0102 and JP21dk0207050h001), JST (Moonshot R&D; Grant Number JPMJMS2024), Grant-in-aid for Research in Nagoya City University (Grant Number 2021101), the Hori Sciences & Arts Foundation, and Toyoaki Scholarship Foundation. AB and KM were supported by VLAIO (HBC.2017.0948). GvL and AB were supported by VLAIO (HBC.2020.3240). MS was supported by the Berta-Ottenstein-Programme for Clinician Scientists, Faculty of Medicine, University of Freiburg, and the IMM-PACT-Programme for Clinician Scientists, Department of Medicine II, Medical Center, University of Freiburg and Faculty of Medicine, University of Freiburg, funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, 413517907). Acknowledgments
Publisher Copyright:
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.