1. β-Amyloid Clustering around ASC Fibrils Boosts Its Toxicity in Microglia.
- Author
-
Friker LL, Scheiblich H, Hochheiser IV, Brinkschulte R, Riedel D, Latz E, Geyer M, and Heneka MT
- Subjects
- Amyloid beta-Peptides metabolism, Amyloid beta-Peptides ultrastructure, Animals, Caspase 1 metabolism, Cells, Cultured, Humans, Inflammasomes metabolism, Interleukin-1beta metabolism, Mice, Inbred C57BL, Microglia drug effects, Microglia metabolism, Models, Biological, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Proteolysis drug effects, Pyroptosis drug effects, Signal Transduction drug effects, Toll-Like Receptor 2 metabolism, Toll-Like Receptor 4 metabolism, Amyloid beta-Peptides toxicity, CARD Signaling Adaptor Proteins metabolism, Microglia pathology
- Abstract
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., Competing Interests: Declaration of Interests 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., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF