NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice
| Autor: | Ellen Gelpi, Annett Halle, Markus P. Kummer, Daisy Axt, Andrea Delekate, Anita Remus, Douglas T. Golenbock, Te-Chen Tzeng, Andrea Stutz, Eicke Latz, Martin Korte, Stephanie Schwartz, Ana Vieira-Saecker, Michael T. Heneka, Angelika Griep |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
physiopathology [Cognitive Dysfunction]
enzymology [Brain] Inflammasomes Interleukin-1beta Nitric Oxide Synthase Type II genetics [Alzheimer Disease] Disease genetics [Carrier Proteins] enzymology [Cognitive Dysfunction] Pathogenesis pathology [Alzheimer Disease] Mice pathology [Brain] genetics [Caspase 1] Regulation of gene expression Aged 80 and over Multidisciplinary Microglia integumentary system Behavior Animal Caspase 1 Brain Inflammasome medicine.anatomical_structure ddc:500 medicine.drug Mild Cognitive Impairment Transgene Nlrp3 protein mouse metabolism [Amyloid beta-Peptides] Mice Transgenic Biology Article Gene Expression Regulation Enzymologic metabolism [Interleukin-1beta] Phagocytosis In vivo Alzheimer Disease Memory NLR Family Pyrin Domain-Containing 3 Protein medicine NLRP3 protein human Animals Humans genetics [Phagocytosis] Neuroinflammation Aged Amyloid beta-Peptides metabolism [Caspase 1] enzymology [Alzheimer Disease] metabolism [Nitric Oxide Synthase Type II] Mice Inbred C57BL Immunology Carrier Proteins metabolism [Inflammasomes] metabolism [Carrier Proteins] |
| Zdroj: | Nature Nature |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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