NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice.
dc.contributor.author | Heneka, Michael T | |
dc.contributor.author | Kummer, Markus P | |
dc.contributor.author | Stutz, Andrea | |
dc.contributor.author | Delekate, Andrea | |
dc.contributor.author | Schwartz, Stephanie | |
dc.contributor.author | Vieira-Saecker, Ana | |
dc.contributor.author | Griep, Angelika | |
dc.contributor.author | Axt, Daisy | |
dc.contributor.author | Remus, Anita | |
dc.contributor.author | Tzeng, Te-Chen | |
dc.contributor.author | Gelpi, Ellen | |
dc.contributor.author | Halle, Annett | |
dc.contributor.author | Korte, Martin | |
dc.contributor.author | Latz, Eicke | |
dc.contributor.author | Golenbock, Douglas T | |
dc.date.accessioned | 2014-09-12T12:03:02Z | |
dc.date.available | 2014-09-12T12:03:02Z | |
dc.date.issued | 2013-01-31 | |
dc.identifier.citation | NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. 2013, 493 (7434):674-8 Nature | en |
dc.identifier.issn | 1476-4687 | |
dc.identifier.pmid | 23254930 | |
dc.identifier.doi | 10.1038/nature11729 | |
dc.identifier.uri | http://hdl.handle.net/10033/326072 | |
dc.description.abstract | 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. | |
dc.language.iso | en | en |
dc.rights | Archived with thanks to Nature | en |
dc.subject.mesh | Aged | en |
dc.subject.mesh | Aged, 80 and over | en |
dc.subject.mesh | Alzheimer Disease | en |
dc.subject.mesh | Amyloid beta-Peptides | en |
dc.subject.mesh | Animals | en |
dc.subject.mesh | Behavior, Animal | en |
dc.subject.mesh | Brain | en |
dc.subject.mesh | Carrier Proteins | en |
dc.subject.mesh | Caspase 1 | en |
dc.subject.mesh | Gene Expression Regulation, Enzymologic | en |
dc.subject.mesh | Humans | en |
dc.subject.mesh | Inflammasomes | en |
dc.subject.mesh | Interleukin-1beta | en |
dc.subject.mesh | Memory | en |
dc.subject.mesh | Mice | en |
dc.subject.mesh | Mice, Inbred C57BL | en |
dc.subject.mesh | Mice, Transgenic | en |
dc.subject.mesh | Mild Cognitive Impairment | en |
dc.subject.mesh | Nitric Oxide Synthase Type II | en |
dc.subject.mesh | Phagocytosis | en |
dc.title | NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. | en |
dc.type | Article | en |
dc.identifier.journal | Nature | en |
refterms.dateFOA | 2018-06-13T15:25:21Z | |
html.description.abstract | 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. |