NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice (original) (raw)

Nature volume 493, pages 674–678 (2013)Cite this article

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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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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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Author notes

  1. Michael T. Heneka, Eicke Latz and Douglas T. Golenbock: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Clinical Neuroscience Unit, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany,
    Michael T. Heneka, Markus P. Kummer, Stephanie Schwartz, Ana Vieira-Saecker, Angelika Griep & Daisy Axt
  2. Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, 53175, Germany
    Michael T. Heneka & Eicke Latz
  3. Institute of Innate Immunity, University of Bonn, Bonn, 53127, Germany
    Andrea Stutz & Eicke Latz
  4. Division of Cellular Neurobiology, Zoological Institute, Technische Universität Braunschweig, Braunschweig, 38106, Germany
    Andrea Delekate, Anita Remus & Martin Korte
  5. Department of Medicine and Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, 01605, Massachusetts, USA
    Te-Chen Tzeng, Eicke Latz & Douglas T. Golenbock
  6. Neurological Tissue Bank, University of Barcelona-Hospital Clinic, IDIBAPS, 08036 Barcelona, Spain,
    Ellen Gelpi
  7. Center for Advanced European Studies and Research-CAESAR, Bonn, 53175, Germany
    Annett Halle
  8. Helmholtz-Center for Infection Research, HZI, AG NIND, 38124 Braunschweig, Germany,
    Martin Korte

Authors

  1. Michael T. Heneka
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  2. Markus P. Kummer
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  3. Andrea Stutz
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  4. Andrea Delekate
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  5. Stephanie Schwartz
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  6. Ana Vieira-Saecker
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  7. Angelika Griep
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  8. Daisy Axt
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  9. Anita Remus
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  10. Te-Chen Tzeng
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  11. Ellen Gelpi
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  12. Annett Halle
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  13. Martin Korte
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  14. Eicke Latz
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  15. Douglas T. Golenbock
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Contributions

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.

Corresponding authors

Correspondence toMichael T. Heneka, Eicke Latz or Douglas T. Golenbock.

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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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Editorial Summary

Inflammasome a target in Alzheimer's disease

Alzheimer's disease is associated with activation of the innate immune system. It is known that amyloid-β can activate the NLRP3 inflammasome in vitro in microglia, and here it is shown that the inflammasome has a critical role in Alzheimer's disease pathology in a mouse model in vivo. In the absence of NLRP3 or caspase-1, amyloidosis and neuropathology in mice is reduced, and cognition and associated electrophysiological parameters improved. Examination of post-mortem human Alzheimer's brains supports the link between NLRP3 and brain inflammation. Taken together, these results suggest that amyloid-β-induced activation of NLRP3 enhances the progression of Alzheimer's disease by mediating a harmful chronic inflammatory tissue post-mortem response, and that agents that block the activity of the NLRP3 inflammasome, or inflammasome-derived cytokines, might slow the progression of Alzheimer's disease.