Article

Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer’s disease

  • Nature volume 552, pages 355361 (21 December 2017)
  • doi:10.1038/nature25158
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Abstract

The spreading of pathology within and between brain areas is a hallmark of neurodegenerative disorders. In patients with Alzheimer’s disease, deposition of amyloid-β is accompanied by activation of the innate immune system and involves inflammasome-dependent formation of ASC specks in microglia. ASC specks released by microglia bind rapidly to amyloid-β and increase the formation of amyloid-β oligomers and aggregates, acting as an inflammation-driven cross-seed for amyloid-β pathology. Here we show that intrahippocampal injection of ASC specks resulted in spreading of amyloid-β pathology in transgenic double-mutant APPSwePSEN1dE9 mice. By contrast, homogenates from brains of APPSwePSEN1dE9 mice failed to induce seeding and spreading of amyloid-β pathology in ASC-deficient APPSwePSEN1dE9 mice. Moreover, co-application of an anti-ASC antibody blocked the increase in amyloid-β pathology in APPSwePSEN1dE9 mice. These findings support the concept that inflammasome activation is connected to seeding and spreading of amyloid-β pathology in patients with Alzheimer’s disease.

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Acknowledgements

This work was funded by the Deutsche Forschungsgemeinschaft through the Cluster of Excellence “Immunosensation” (to M.T.H., E.L., M.G. and B.S.F.), the Clinical Research Group (KFO177; to M.T.H., E.L. and J.W.), the SFB670 (E.L.), grant WA1477/6 (J.W.), ERC InflammAct (E.L.), ERC PLAT-IL-1 (B.S.F.), the ERA-NET consortium TracInflam (M.T.H.) and JPND consortium InCure (M.T.H.).

Author information

Author notes

    • Carmen Venegas
    •  & Sathish Kumar

    These authors contributed equally to this work.

Affiliations

  1. Department of Neurodegenerative Diseases and Gerontopsychiatry, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany

    • Carmen Venegas
    • , Tobias Dierkes
    • , Dario Tejera
    • , Ana Vieira-Saecker
    • , Stephanie Schwartz
    • , Francesco Santarelli
    • , Markus P. Kummer
    • , Angelika Griep
    •  & Michael T. Heneka
  2. Department of Neurology, University of Bonn, 53127 Bonn, Germany

    • Sathish Kumar
    •  & Jochen Walter
  3. Institute of Innate Immunity, University of Bonn, 53127 Bonn, Germany

    • Bernardo S. Franklin
    • , Tobias Dierkes
    • , Rebecca Brinkschulte
    • , Michael Beilharz
    • , Matthias Geyer
    •  & Eicke Latz
  4. Neurological Tissue Bank, University of Barcelona-Hospital Clinic, IDIBAPS, 08036 Barcelona, Spain

    • Ellen Gelpi
  5. Electron Microscopy Group, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany

    • Dietmar Riedel
  6. Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA

    • Douglas T. Golenbock
    • , Eicke Latz
    •  & Michael T. Heneka
  7. Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 53127 Bonn, Germany

    • Eicke Latz
    •  & Michael T. Heneka

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Contributions

C.V., S.K., B.S.F., T.D., R.B., D.T., A.V.-S., S.S., F.S., A.G., D.R., M.G., M.B., E.L. and M.T.H. performed experiments and analysed data. S.K., M.P.K., E.G., D.T.G., J.W. and M.T.H. designed the study and wrote the paper. Results were discussed and the manuscript was commented on by all authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Michael T. Heneka.

Reviewer Information Nature thanks R. Ransohoff, G. Nunez and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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    This file contains Supplementary Figures 1-3, the uncropped gels.

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    Life Sciences Reporting Summary

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