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

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 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 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 and 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 mice and Nlrp3 deletion in 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.