Abstract
Alzheimer’s disease is the world’s most common dementing illness. Deposition of amyloid-β peptide drives cerebral neuroinflammation by activating microglia1,2. 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.
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Change history
30 January 2013
Minor corrections were made to Fig. 2d and the legend to Fig. 3.
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Acknowledgements
This work was funded by the Dana Foundation (E.L.), the National Institutes of Health (E.L., D.T.G.) and the Deutsche Forschungsgemeinschaft (E.L., M.T.H.). We thank G. Nuñez and V. M. Dixit for providing anti-caspase-1 Abs. We thank B. De Strooper and L. Serneels for the BACE1 knockout mice and discussion. We also thank H. Jacobsen for the BACE1 transgenic mice.
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M.T.H, M.P.K, A.S., A.D., S.S., A.V.-S., A.G., D.A., A.R., T.T. and E.L. performed experiments and analysed data, E.G. provided human samples and analysed data, A.H. was involved in study design and analysed data, E.L., M.T.H., M.K. and D.T.G. designed the study and wrote the paper. All authors discussed results and commented on the manuscript.
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Heneka, M., Kummer, M., Stutz, A. et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493, 674–678 (2013). https://doi.org/10.1038/nature11729
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DOI: https://doi.org/10.1038/nature11729
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