NLRP3 & Alzheimer

NATURE | LETTER

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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
• & Douglas T. Golenbock

• Affiliations
• Contributions
• Corresponding authors

Nature

 

(2012)

 
Alzheimer’s disease is the world’s most common dementing illness. Deposition of amyloid-β peptide drives cerebral neuroinflammation by activating microglia^1, 2. Indeed, amyloid-β activation of the NLRP3 inflammasome in microglia is fundamental for interleukin-1β maturation and subsequent inflammatory events³. 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.At a glance

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