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

Carmen Venegas, Sathish Kumar, Bernardo S. Franklin, Tobias Dierkes, Rebecca Brinkschulte, Dario Tejera, Ana Vieira-Saecker, Stephanie Schwartz, Francesco Santarelli, Markus P. Kummer, Angelika Griep, Ellen Gelpi, Michael Beilharz, Dietmar Riedel, Douglas T. Golenbock, Matthias Geyer, Jochen Walter, Eicke Latz and Michael T. Heneka ()
Additional contact information
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
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
Michael T. Heneka: University of Bonn

Nature, 2017, vol. 552, issue 7685, 355-361

Abstract: 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.

Date: 2017
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DOI: 10.1038/nature25158

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