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

Author

Listed:
  • Carmen Venegas

    (University of Bonn)

  • Sathish Kumar

    (University of Bonn)

  • Bernardo S. Franklin

    (Institute of Innate Immunity, University of Bonn)

  • Tobias Dierkes

    (University of Bonn
    Institute of Innate Immunity, University of Bonn)

  • Rebecca Brinkschulte

    (Institute of Innate Immunity, University of Bonn)

  • Dario Tejera

    (University of Bonn)

  • Ana Vieira-Saecker

    (University of Bonn)

  • Stephanie Schwartz

    (University of Bonn)

  • Francesco Santarelli

    (University of Bonn)

  • Markus P. Kummer

    (University of Bonn)

  • Angelika Griep

    (University of Bonn)

  • Ellen Gelpi

    (Neurological Tissue Bank, University of Barcelona-Hospital Clinic, IDIBAPS)

  • Michael Beilharz

    (Institute of Innate Immunity, University of Bonn)

  • Dietmar Riedel

    (Electron Microscopy Group, Max Planck Institute for Biophysical Chemistry)

  • Douglas T. Golenbock

    (University of Massachusetts Medical School)

  • Matthias Geyer

    (Institute of Innate Immunity, University of Bonn)

  • Jochen Walter

    (University of Bonn)

  • Eicke Latz

    (Institute of Innate Immunity, University of Bonn
    University of Massachusetts Medical School
    Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE))

  • Michael T. Heneka

    (University of Bonn
    University of Massachusetts Medical School
    Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE))

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.

Suggested Citation

  • Carmen Venegas & Sathish Kumar & Bernardo S. Franklin & Tobias Dierkes & Rebecca Brinkschulte & Dario Tejera & Ana Vieira-Saecker & Stephanie Schwartz & Francesco Santarelli & Markus P. Kummer & Angel, 2017. "Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer’s disease," Nature, Nature, vol. 552(7685), pages 355-361, December.
    • Handle: RePEc:nat:nature:v:552:y:2017:i:7685:d:10.1038_nature25158
    DOI: 10.1038/nature25158
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    Cited by:

    1. Evgeniia Lobanova & Yu P. Zhang & Derya Emin & Jack Brelstaff & Lakmini Kahanawita & Maura Malpetti & Annelies Quaegebeur & Kathy Triantafilou & Martha Triantafilou & Henrik Zetterberg & James B. Rowe, 2024. "ASC specks as a single-molecule fluid biomarker of inflammation in neurodegenerative diseases," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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