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

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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Figure 1: Protective effects of NLRP3 gene deficiency in APP/PS1 mice on memory and behaviour.
Figure 2: NLRP3 gene deficiency leads to decreased amyloid-β amounts and deposition.
Figure 3: NLRP3 or caspase-1 deficiency increases microglial amyloid-β phagocytosis.
Figure 4: NLRP3 gene deficiency conveys a M2 microglial phenotype, decreases NOS2 expression and strongly reduces 3NTyr-amyloid-β formation.

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  • 30 January 2013

    Minor corrections were made to Fig. 2d and the legend to Fig. 3.

References

  1. Prinz, M., Priller, J., Sisodia, S. S. & Ransohoff, R. M. Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nature Neurosci. 14, 1227–1235 (2011)

    Article  CAS  Google Scholar 

  2. Lucin, K. M. & Wyss-Coray, T. Immune activation in brain aging and neurodegeneration: too much or too little? Neuron 64, 110–122 (2009)

    Article  CAS  Google Scholar 

  3. Halle, A. et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nature Immunol. 9, 857–865 (2008)

    Article  CAS  Google Scholar 

  4. Martinon, F., Mayor, A. & Tschopp, J. The inflammasomes: guardians of the body. Annu. Rev. Immunol. 27, 229–265 (2009)

    Article  CAS  Google Scholar 

  5. Jankowsky, J. L. et al. Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol. Eng. 17, 157–165 (2001)

    Article  CAS  Google Scholar 

  6. Bliss, T. V. & Collingridge, G. L. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31–39 (1993)

    Article  ADS  CAS  Google Scholar 

  7. Ho, V. M., Lee, J.-A. & Martin, K. C. The cell biology of synaptic plasticity. Science 334, 623–628 (2011)

    Article  ADS  CAS  Google Scholar 

  8. Walker, J. M. et al. Spatial learning and memory impairment and increased locomotion in a transgenic amyloid precursor protein mouse model of Alzheimer’s disease. Behav. Brain Res. 222, 169–175 (2011)

    Article  ADS  CAS  Google Scholar 

  9. Heneka, M. T. & O’Banion, M. K. Inflammatory processes in Alzheimer’s disease. J. Neuroimmunol. 184, 69–91 (2007)

    Article  CAS  Google Scholar 

  10. Lee, C. Y. D. & Landreth, G. E. The role of microglia in amyloid clearance from the AD brain. J. Neural Transm. 117, 949–960 (2010)

    Article  CAS  Google Scholar 

  11. Nalbantoglu, J. et al. Impaired learning and LTP in mice expressing the carboxy terminus of the Alzheimer amyloid precursor protein. Nature 387, 500–505 (1997)

    Article  CAS  Google Scholar 

  12. Chapman, P. F. et al. Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice. Nature Neurosci. 2, 271–276 (1999)

    Article  CAS  Google Scholar 

  13. Murray, C. A. & Lynch, M. A. Evidence that increased hippocampal expression of the cytokine interleukin-1β is a common trigger for age- and stress-induced impairments in long-term potentiation. J. Neurosci. 18, 2974–2981 (1998)

    Article  CAS  Google Scholar 

  14. El Khoury, J. et al. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nature Med. 13, 432–438 (2007)

    Article  CAS  Google Scholar 

  15. Bamberger, M. E., Harris, M. E., McDonald, D. R., Husemann, J. & Landreth, G. E. A cell surface receptor complex for fibrillar β-amyloid mediates microglial activation. J. Neurosci. 23, 2665–2674 (2003)

    Article  CAS  Google Scholar 

  16. Hickman, S. E., Allison, E. K. & Khoury, J. E. Microglial dysfunction and defective β-amyloid clearance pathways in aging Alzheimer’s disease mice. J. Neurosci. 28, 8354–8360 (2008)

    Article  CAS  Google Scholar 

  17. Heneka, M. T. et al. Locus ceruleus controls Alzheimer’s disease pathology by modulating microglial functions through norepinephrine. Proc. Natl Acad. Sci. USA 107, 6058–6063 (2010)

    Article  ADS  CAS  Google Scholar 

  18. Shaftel, S. S. et al. Sustained hippocampal IL-1β overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology. J. Clin. Invest. 117, 1595–1604 (2007)

    Article  CAS  Google Scholar 

  19. Shaftel, S. S. et al. Chronic interleukin-1β expression in mouse brain leads to leukocyte infiltration and neutrophil-independent blood brain barrier permeability without overt neurodegeneration. J. Neurosci. 27, 9301–9309 (2007)

    Article  CAS  Google Scholar 

  20. Mildner, A. et al. Distinct and non-redundant roles of microglia and myeloid subsets in mouse models of Alzheimer’s disease. J. Neurosci. 31, 11159–11171 (2011)

    Article  CAS  Google Scholar 

  21. Malito, E., Hulse, R. E. & Tang, W.-J. Amyloid β-degrading cryptidases: insulin degrading enzyme, neprilysin, and presequence peptidase. Cell. Mol. Life Sci. 65, 2574–2585 (2008)

    Article  CAS  Google Scholar 

  22. Leissring, M. A. et al. Enhanced proteolysis of β-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron 40, 1087–1093 (2003)

    Article  CAS  Google Scholar 

  23. Mawuenyega, K. G. et al. Decreased clearance of CNS β-amyloid in Alzheimer’s disease. Science 330, 1774 (2010)

    Article  ADS  CAS  Google Scholar 

  24. Raes, G. et al. FIZZ1 and Ym as tools to discriminate between differentially activated macrophages. Dev. Immunol. 9, 151–159 (2002)

    Article  CAS  Google Scholar 

  25. Kummer, M. P. et al. Nitration of tyrosine 10 critically enhances amyloid β aggregation and plaque formation. Neuron 71, 833–844 (2011)

    Article  CAS  Google Scholar 

  26. Wang, Q., Rowan, M. J. & Anwyl, R. β-Amyloid-mediated inhibition of NMDA receptor-dependent long-term potentiation induction involves activation of microglia and stimulation of inducible nitric oxide synthase and superoxide. J. Neurosci. 24, 6049–6056 (2004)

    Article  CAS  Google Scholar 

  27. Kanneganti, T.-D. et al. Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 440, 233–236 (2006)

    Article  ADS  CAS  Google Scholar 

  28. Li, P. et al. Mice deficient in IL-1 β-converting enzyme are defective in production of mature IL-1β and resistant to endotoxic shock. Cell 80, 401–411 (1995)

    Article  CAS  Google Scholar 

  29. Bevins, R. A. & Besheer, J. Object recognition in rats and mice: a one-trial non-matching-to-sample learning task to study ‘recognition memory’. Nature Protocols 1, 1306–1311 (2006)

    Article  Google Scholar 

  30. Jäger, S. et al. alpha-secretase mediated conversion of the amyloid precursor protein derived membrane stub C99 to C83 limits Aβ generation. J. Neurochem. 111, 1369–1382 (2009)

    Article  Google Scholar 

Download references

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

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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 to Michael T. Heneka, Eicke Latz or Douglas T. Golenbock.

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The authors declare no competing financial interests.

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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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