Nature (London), 2013-01, Vol.493 (7434), p.674-678
2013
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Details
- Autor(en) / Beteiligte
- Titel
- NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice
- Ist Teil von
- Nature (London), 2013-01, Vol.493 (7434), p.674-678
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2013
- Quelle
- EBSCO - Psychology & Behavioral Sciences Collection
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0028-0836eISSN: 1476-4687DOI: 10.1038/nature11729Titel-ID: cdi_proquest_miscellaneous_1283730057
- Format
- –
- Schlagworte
- Aged, Aged, 80 and over, Alzheimer Disease - enzymology, Alzheimer Disease - genetics, Alzheimer Disease - pathology, Alzheimer's disease, Amyloid beta-Peptides - metabolism, Animal cognition, Animals, Behavior, Animal, Brain, Brain - enzymology, Brain - pathology, Carrier Proteins - genetics, Carrier Proteins - metabolism, Caspase 1 - genetics, Caspase 1 - metabolism, Cognitive ability, Cognitive Dysfunction - enzymology, Cognitive Dysfunction - physiopathology, Cytokines, Development and progression, Gene Expression Regulation, Enzymologic, Genetic aspects, Genotype & phenotype, Humans, Inflammasomes - metabolism, Interleukin-1beta - metabolism, Memory, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Nitric oxide, Nitric Oxide Synthase Type II - metabolism, NLR Family, Pyrin Domain-Containing 3 Protein, Pathogenesis, Pathology, Phagocytosis - genetics, Proteins, Rodents