[en] Alzheimer's disease is the world's most common neurodegenerative disorder. It is associated with neuroinflammation involving activation of microglia by β-amyloid (Aβ) deposits. Based on previous studies showing apoptosis-associated speck-like protein containing a CARD (ASC) binding and cross-seeding extracellular Aβ, we investigate the propagation of ASC between primary microglia and the effects of ASC-Aβ composites on microglial inflammasomes and function. Indeed, ASC released by a pyroptotic cell can be functionally built into the neighboring microglia NOD-like receptor protein (NLRP3) inflammasome. Compared with protein-only application, exposure to ASC-Aβ composites amplifies the proinflammatory response, resulting in pyroptotic cell death, setting free functional ASC and inducing a feedforward stimulating vicious cycle. Clustering around ASC fibrils also compromises clearance of Aβ by microglia. Together, these data enable a closer look at the turning point from acute to chronic Aβ-related neuroinflammation through formation of ASC-Aβ composites.
Disciplines :
Neurology
Author, co-author :
Friker, Lea L; Department of Neurodegenerative Disease and Gerontopsychiatry/Neurology, University of Bonn Medical Center, 53127 Bonn, Germany
Scheiblich, Hannah; Department of Neurodegenerative Disease and Gerontopsychiatry/Neurology, University of Bonn Medical Center, 53127 Bonn, Germany
Hochheiser, Inga V; Institute of Structural Biology, University of Bonn, 53127 Bonn, Germany
Brinkschulte, Rebecca; Institute of Structural Biology, University of Bonn, 53127 Bonn, Germany
Riedel, Dietmar; Max Planck Institute for Biophysical Chemistry, Department of Structural Dynamics, 37077 Göttingen, Germany
Latz, Eicke; Institute of Innate Immunity, University of Bonn, 53127 Bonn, Germany
Geyer, Matthias; Institute of Structural Biology, University of Bonn, 53127 Bonn, Germany
HENEKA, Michael ; University of Bonn Medical Center, 53127 Bonn, Germany > epartment of Neurodegenerative Disease and Gerontopsychiatry/Neurology ; German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany ; University of Massachusetts Medical School, Worcester, MA 01655, USA > Department of Infectious Diseases and Immunology
External co-authors :
yes
Language :
English
Title :
β-Amyloid Clustering around ASC Fibrils Boosts Its Toxicity in Microglia.
Deutsche Forschungsgemeinschaft National Institutes of Health Deutsche Forschungsgemeinschaft
Funding text :
This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy – EXC2151 – 390873048 . M.T.H. received further funding from the NIH grant ( R01 AG059752-02 ). The authors thank Tobias Dierkes for chemical compound and cell line exchange between the groups. We would particularly like to thank the Germen Center for Neurodegenerative Disease within the Helmholtz Association (DZNE) in Bonn, Germany for providing laboratory premises and facilities.This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy ? EXC2151 ? 390873048. M.T.H. received further funding from the NIH grant (R01 AG059752-02). The authors thank Tobias Dierkes for chemical compound and cell line exchange between the groups. We would particularly like to thank the Germen Center for Neurodegenerative Disease within the Helmholtz Association (DZNE) in Bonn, Germany for providing laboratory premises and facilities. Conceptualization, L.L.F. and M.T.H.; Methodology, L.L.F. H.S. and M.T.H.; Investigation, L.L.F. H.S. I.V.H. R.B. and D.R.; Writing ? Original Draft, L.L.F. H.S. R.B. and M.T.H.; Writing ? Review & Editing, L.L.F. H.S. and M.T.H.; Funding Acquisition, M.T.H.; Resources, D.R. E.L. M.G. and M.T.H.; Supervision, M.T.H. Michael T. Heneka serves as an advisory board member at IFM Therapeutics, Alector, and Tiaki. He received honoraria for oral presentations from Novartis, Roche, and Biogen. The authors declare that there is no conflict of interest with regard to the experimental part of this study.
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