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-? peptide drives cerebral neuroinflammation by activating microglia. Indeed, amyloid-? activation of the NLRP3 inflammasome in microglia is fundamental for interleukin-1? 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-1? activation as well as enhanced amyloid-? clearance. Furthermore, NLRP3 inflammasome deficiency skewed microglial cells to an M2 phenotype and resulted in the decreased deposition of amyloid-? 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.

SUBMITTER: Heneka MT 

PROVIDER: S-EPMC3812809 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature