title: NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice.
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.
authors.affiliation: Clinical Neuroscience Unit, Department of Neurology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany. michael.Heneka@ukb.uni-bonn.de
authors.forename: Michael T
authors.initials: MT
authors.lastname: Heneka
authors.forename: Markus P
authors.initials: MP
authors.lastname: Kummer
authors.forename: Andrea
authors.initials: A
authors.lastname: Stutz
authors.forename: Andrea
authors.initials: A
authors.lastname: Delekate
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schwartz
authors.forename: Ana
authors.initials: A
authors.lastname: Vieira-Saecker
authors.forename: Angelika
authors.initials: A
authors.lastname: Griep
authors.forename: Daisy
authors.initials: D
authors.lastname: Axt
authors.forename: Anita
authors.initials: A
authors.lastname: Remus
authors.forename: Te-Chen
authors.initials: TC
authors.lastname: Tzeng
authors.forename: Ellen
authors.initials: E
authors.lastname: Gelpi
authors.forename: Annett
authors.initials: A
authors.lastname: Halle
authors.forename: Martin
authors.initials: M
authors.lastname: Korte
authors.forename: Eicke
authors.initials: E
authors.lastname: Latz
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Golenbock
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000201:enzymology / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000201:enzymology / Q000503:physiopathology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008568:Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010587:Phagocytosis / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; D052247:Nitric Oxide Synthase Type II; D020170:Caspase 1