NLRP3 is activated in Alzheimer´s disease and contributes to pathology in APP/PS1 mice

By Michael T. Heneka, Markus P Kummer, A. Stutz, Andrea Delekate, S. Schwartz, A. Saecker, A. Griep, Daisy Axt, Anita Remus, T. Tzeng and 5 more. Nature, 2012

2,585 citations recorded by the source corpus.

Alzheimer’s disease is the world’s most common dementing illness. Deposition of amyloid-β peptide drives cerebral neuroinflammation by activating microglia. Indeed, amyloid-β activation of the NLRP3 inflammasome in microglia is fundamental for interleukin-1β maturation and subsequent inflammatory events. However, it remains unknown whether NLRP3 activation contributes to Alzheimer’s disease in vivo. Here we demonstrate strongly enhanced active caspase-1 expression in human mild cognitive impairment and brains with Alzheimer’s disease, suggesting a role for the inflammasome in this neurodegenerative disease. Nlrp3−/− or Casp1−/− mice carrying mutations associated with familial Alzheimer’s disease were largely protected from loss of spatial memory and other sequelae associated with Alzheimer’s disease, and demonstrated reduced brain caspase-1 and interleukin-1β activation as well as enhanced amyloid-β clearance. Furthermore, NLRP3 inflammasome deficiency skewed microglial cells to an M2 phenotype and resulted in the decreased deposition of amyloid-β in the APP/PS1 model of Alzheimer’s disease. These results show an important role for the NLRP3/caspase-1 axis in the pathogenesis of Alzheimer’s disease, and suggest that NLRP3 inflammasome inhibition represents a new therapeutic intervention for the disease.

Subfields: Molecular Biology, Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/3a962c33176c94bc0dd8bfea4ebe2eb83be8a01e

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Citations in the corpus

TYROBP in Alzheimer’s Disease (2015, background): “Recent studies have brought microglia again to the stage of the controversial role of inflammation in AD [7, 52].”
Role of neuroinflammation in neurodegeneration development (2023, methodology): “In APP/PS1 mice model, NLRP3 knockout reduced Aβ deposition by enhancing phagocytic clearance capacity and increasing extracellular Aβ degradation by insulin- degrading enzyme (IDE).(354) Using the same model, Dempsey et al.”
TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques (2016, methodology): “Brains were isolated 3 h after injection and made into single-cell suspension as previously described (Heneka et al., 2013).”
Role of pro-inflammatory cytokines released from microglia in Alzheimer's disease. (2015, background): “revealed that inhibition of NLRP3 can induce microglial phagocytosis and to an M2 phenotype (21).”
CD36 coordinates NLRP3 inflammasome activation by facilitating the intracellular nucleation from soluble to particulate ligands in sterile inflammation (2013, background): “In the AD brain and diabetic pancreas, amyloid plaques arise from the aggregation of pre-fibrillar amyloidogenic peptides such as the Aβ(1-42) peptide17, 18, 19 or IAPP20, 21, 22, which oligomerize and give rise to higher order structures, including fibrils.”