期刊
NATURE
卷 493, 期 7434, 页码 674-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature11729
关键词
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资金
- Dana Foundation
- National Institutes of Health
- Deutsche Forschungsgemeinschaft
Alzheimer's disease is the world's most common dementing illness. Deposition of amyloid-beta peptide drives cerebral neuroinflammation by activating microglia(1,2). Indeed, amyloid-beta activation of the NLRP3 inflammasome in microglia is fundamental for interleukin-1 beta maturation and subsequent inflammatory events(3). 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-1 beta 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.
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