2.50
Hdl Handle:
http://hdl.handle.net/10033/326072
Title:
NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice.
Authors:
Heneka, Michael T; Kummer, Markus P; Stutz, Andrea; Delekate, Andrea; Schwartz, Stephanie; Vieira-Saecker, Ana; Griep, Angelika; Axt, Daisy; Remus, Anita; Tzeng, Te-Chen; Gelpi, Ellen; Halle, Annett; Korte, Martin; Latz, Eicke; Golenbock, Douglas T
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.
Citation:
NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. 2013, 493 (7434):674-8 Nature
Journal:
Nature
Issue Date:
31-Jan-2013
URI:
http://hdl.handle.net/10033/326072
DOI:
10.1038/nature11729
PubMed ID:
23254930
Type:
Article
Language:
en
ISSN:
1476-4687
Appears in Collections:
publications of the research group neuroinflammation and neurodegeneration (NIND)

Full metadata record

DC FieldValue Language
dc.contributor.authorHeneka, Michael Ten
dc.contributor.authorKummer, Markus Pen
dc.contributor.authorStutz, Andreaen
dc.contributor.authorDelekate, Andreaen
dc.contributor.authorSchwartz, Stephanieen
dc.contributor.authorVieira-Saecker, Anaen
dc.contributor.authorGriep, Angelikaen
dc.contributor.authorAxt, Daisyen
dc.contributor.authorRemus, Anitaen
dc.contributor.authorTzeng, Te-Chenen
dc.contributor.authorGelpi, Ellenen
dc.contributor.authorHalle, Annetten
dc.contributor.authorKorte, Martinen
dc.contributor.authorLatz, Eickeen
dc.contributor.authorGolenbock, Douglas Ten
dc.date.accessioned2014-09-12T12:03:02Z-
dc.date.available2014-09-12T12:03:02Z-
dc.date.issued2013-01-31-
dc.identifier.citationNLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. 2013, 493 (7434):674-8 Natureen
dc.identifier.issn1476-4687-
dc.identifier.pmid23254930-
dc.identifier.doi10.1038/nature11729-
dc.identifier.urihttp://hdl.handle.net/10033/326072-
dc.description.abstractAlzheimer'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.en
dc.language.isoenen
dc.rightsArchived with thanks to Natureen
dc.subject.meshAgeden
dc.subject.meshAged, 80 and overen
dc.subject.meshAlzheimer Diseaseen
dc.subject.meshAmyloid beta-Peptidesen
dc.subject.meshAnimalsen
dc.subject.meshBehavior, Animalen
dc.subject.meshBrainen
dc.subject.meshCarrier Proteinsen
dc.subject.meshCaspase 1en
dc.subject.meshGene Expression Regulation, Enzymologicen
dc.subject.meshHumansen
dc.subject.meshInflammasomesen
dc.subject.meshInterleukin-1betaen
dc.subject.meshMemoryen
dc.subject.meshMiceen
dc.subject.meshMice, Inbred C57BLen
dc.subject.meshMice, Transgenicen
dc.subject.meshMild Cognitive Impairmenten
dc.subject.meshNitric Oxide Synthase Type IIen
dc.subject.meshPhagocytosisen
dc.titleNLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice.en
dc.typeArticleen
dc.identifier.journalNatureen

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