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NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice.
Heneka, Michael T Kummer, Markus P Stutz, Andrea Delekate, Andrea Schwartz, Stephanie Vieira-Saecker, Ana Griep, Angelika Axt, Daisy Remus, Anita Tzeng, Te-Chen
Heneka, Michael T
Kummer, Markus P
Stutz, Andrea
Delekate, Andrea
Schwartz, Stephanie
Vieira-Saecker, Ana
Griep, Angelika
Axt, Daisy
Remus, Anita
Tzeng, Te-Chen
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2013-01-31
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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.
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NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. 2013, 493 (7434):674-8 Nature
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en
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1476-4687
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Archived with thanks to Nature