AUTHOR=Srinivasan Sahana , Kancheva Daliya , De Ren Sofie , Saito Takashi , Jans Maude , Boone Fleur , Vandendriessche Charysse , Paesmans Ine , Maurin Hervé , Vandenbroucke Roosmarijn E. , Hoste Esther , Voet Sofie , Scheyltjens Isabelle , Pavie Benjamin , Lippens Saskia , Schwabenland Marius , Prinz Marco , Saido Takaomi , Bottelbergs Astrid , Movahedi Kiavash , Lamkanfi Mohamed , van Loo Geert
TITLE=Inflammasome signaling is dispensable for ß-amyloid-induced neuropathology in preclinical models of Alzheimer’s disease
JOURNAL=Frontiers in Immunology
VOLUME=15
YEAR=2024
URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1323409
DOI=10.3389/fimmu.2024.1323409
ISSN=1664-3224
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.