• Nature · Jan 2013

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

    • Michael T Heneka, Markus P Kummer, Andrea Stutz, Andrea Delekate, Stephanie Schwartz, Ana Vieira-Saecker, Angelika Griep, Daisy Axt, Anita Remus, Te-Chen Tzeng, Ellen Gelpi, Annett Halle, Martin Korte, Eicke Latz, and Douglas T Golenbock.
    • Clinical Neuroscience Unit, Department of Neurology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany. michael.Heneka@ukb.uni-bonn.de
    • Nature. 2013 Jan 31; 493 (7434): 674-8.

    AbstractAlzheimer's disease is the world's most common dementing illness. Deposition of amyloid-β peptide drives cerebral neuroinflammation by activating microglia. Indeed, amyloid-β activation of the NLRP3 inflammasome in microglia is fundamental for interleukin-1β 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-1β activation as well as enhanced amyloid-β clearance. Furthermore, NLRP3 inflammasome deficiency skewed microglial cells to an M2 phenotype and resulted in the decreased deposition of amyloid-β 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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