Michael T. Heneka 1 , 3 , # , Markus P. Kummer 1 , Andrea Stutz 2 , Andrea Delekate 4 , Stephanie Schwartz 1 , Ana Saecker 1 , Angelika Griep 1 , Daisy Axt 1 , Anita Remus 4 , Te-Chen Tzeng 5 , Ellen Gelpi 6 , Annett Halle 7 , Martin Korte 4 , Eicke Latz 2 , 3 , 5 , # , Douglas Golenbock 5 , #
19 December 2012
Alzheimer´s Disease (AD) is the world’s most common dementing illness. Deposition of amyloid beta peptide (Aβ) drives cerebral neuroinflammation by activating microglia 1, 2 . Indeed, Aβ activation of the NLRP3 inflammasome in microglia is fundamental for IL-1β maturation and subsequent inflammatory events 3 . However, it remains unknown whether NLRP3 activation contributes to AD in vivo. Here, we demonstrate strongly enhanced active caspase-1 expression in human MCI and AD brains suggesting a role for the inflammasome in this neurodegenerative disease. NLRP3 −/− or caspase-1 −/− mice carrying mutations associated with familiar AD were largely protected from loss of spatial memory and other AD-associated sequelae and demonstrated reduced brain caspase-1 and IL-1β activation as well as enhanced Aβ clearance. Furthermore, NLRP3 inflammasome deficiency skewed microglial cells to an M2 phenotype and resulted in the decreased deposition of Aβ in the APP/PS1 model of Alzheimer’s disease. These results reveal an important role for the NLRP3 / caspase-1 axis in AD pathogenesis, and suggest that NLRP3 inflammasome inhibition represents a novel therapeutic intervention for AD.