1. Inflammasome signaling is dispensable for ß-amyloid-induced neuropathology in preclinical models of Alzheimer’s disease
- Author
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Sahana Srinivasan, Daliya Kancheva, Sofie De Ren, Takashi Saito, Maude Jans, Fleur Boone, Charysse Vandendriessche, Ine Paesmans, Hervé Maurin, Roosmarijn E. Vandenbroucke, Esther Hoste, Sofie Voet, Isabelle Scheyltjens, Benjamin Pavie, Saskia Lippens, Marius Schwabenland, Marco Prinz, Takaomi Saido, Astrid Bottelbergs, Kiavash Movahedi, Mohamed Lamkanfi, and Geert van Loo
- Subjects
Alzheimer’s disease ,ß-amyloid ,microglia ,neuroinflammation ,inflammasome ,Immunologic diseases. Allergy ,RC581-607 - Abstract
BackgroundAlzheimer’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.MethodsHere, we evaluated the in vivo role of microglia-selective and full body inflammasome signalling in several mouse models of ß-amyloid-induced AD neuropathology.ResultsMicroglia-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.ConclusionCollectively, these results question a generalizable role for inflammasome activation in preclinical amyloid-only models of neuroinflammation.
- Published
- 2024
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