[en] Alzheimer'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.
Disciplines :
Neurology
Author, co-author :
HENEKA, Michael ; Clinical Neuroscience Unit, Department of Neurology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany. michael.Heneka@ukb.uni-bonn.de
Kummer, Markus P; Clinical Neuroscience Unit, Department of Neurology, University of Bonn, 53127 Bonn, Germany
Stutz, Andrea; Institute of Innate Immunity, University of Bonn, 53127 Bonn, Germany
Delekate, Andrea; Division of Cellular Neurobiology, Zoological Institute, Technische Universität Braunschweig, 38106 Braunschweig, Germany
Schwartz, Stephanie; Clinical Neuroscience Unit, Department of Neurology, University of Bonn, 53127 Bonn, Germany
Vieira-Saecker, Ana; Clinical Neuroscience Unit, Department of Neurology, University of Bonn, 53127 Bonn, Germany
Griep, Angelika; Clinical Neuroscience Unit, Department of Neurology, University of Bonn, 53127 Bonn, Germany
Axt, Daisy; Clinical Neuroscience Unit, Department of Neurology, University of Bonn, 53127 Bonn, Germany
Remus, Anita; Division of Cellular Neurobiology, Zoological Institute, Technische Universität Braunschweig, 38106 Braunschweig, Germany
Tzeng, Te-Chen; Department of Medicine and Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, United States
Gelpi, Ellen; Neurological Tissue Bank, University of Barcelona-Hospital Clinic, IDIBAPS, 08036 Barcelona, Spain
Halle, Annett; Center for Advanced European Studies and Research-CAESAR, 53175 Bonn, Germany
Korte, Martin; Division of Cellular Neurobiology, Zoological Institute, Technische Universität Braunschweig, 38106 Braunschweig, Germany ; Helmholtz-Center for Infection Research, HZI, AG NIND, 38124 Braunschweig, Germany
Latz, Eicke; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 53175 Bonn, Germany ; Institute of Innate Immunity, University of Bonn, 53127 Bonn, Germany ; Department of Medicine and Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, United States
Golenbock, Douglas T; Department of Medicine and Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, United States
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