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

Heneka, M. T.; Kummer, M. P.; Stutz, A.; Delekate, A.; Schwartz, S.; Vieira-Saecker, A.; Griep, A.; Axt, D.; Remus, A.; Tzeng, T. C.; Gelpi, E.; Halle, A.; Korte, M.; Latz, E.; Golenbock, D. T.

doi:10.1038/nature11729

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

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Halle, A.
Max Planck Research Group Neuroimmunology, Center of Advanced European Studies and Research (caesar), Max Planck Society;

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http://www.ncbi.nlm.nih.gov/pubmed/23254930
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http://www.nature.com/nature/journal/v493/n7434/pdf/nature11729.pdf
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Heneka, M. T., Kummer, M. P., Stutz, A., Delekate, A., Schwartz, S., Vieira-Saecker, A., et al. (2013). NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature, 493(7434), 674-678. doi:10.1038/nature11729.

Cite as: https://hdl.handle.net/11858/00-001M-0000-0028-617F-E

Abstract

Alzheimer's disease is the world's most common dementing illness. Deposition of amyloid-beta peptide drives cerebral neuroinflammation by activating microglia. Indeed, amyloid-beta activation of the NLRP3 inflammasome in microglia is fundamental for interleukin-1beta 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-1beta activation as well as enhanced amyloid-beta clearance. Furthermore, NLRP3 inflammasome deficiency skewed microglial cells to an M2 phenotype and resulted in the decreased deposition of amyloid-beta 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.