NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice

Article

关键词: LONG-TERM POTENTIATION;    AMYLOID CLEARANCE;    BETA;    MICROGLIA;    CNS;    INTERLEUKIN-1-BETA;    EXPRESSION;    IL-1-BETA;    ENZYME;    MEMORY;   

DOI  :  10.1038/nature11729

来源: SCIE

【 摘 要 】

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.

【 授权许可】

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