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

  • Srinivasan, Sahana
  • Kancheva, Daliya
  • De Ren, Sofie
  • Saito, Takashi
  • Jans, Maude
  • Boone, Fleur
  • Vandendriessche, Charysse
  • Paesmans, Ine
  • Maurin, Herve
  • Vandenbroucke, Roosmarijn
  • Hoste, Esther
  • Voet, Sofie
  • Scheyltjens, Isabelle
  • Pavie, Benjamin
  • Lippens, Saskia
  • Schwabenland, Marius
  • Prinz, Marco
  • Saido, Takaomi
  • Bottelbergs, Astrid
  • Movahedi, Kiavash
  • And 2 more
Publication Date
Jan 01, 2024
Ghent University Institutional Archive
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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.

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