Cell Rep. 2020 Mar 17;30(11):3743-3754.e6. doi: 10.1016/j.celrep.2020.02.025.
1 Department of Neurodegenerative Disease and Gerontopsychiatry/Neurology, University of Bonn Medical Center, 53127 Bonn, Germany.
2 Institute of Structural Biology, University of Bonn, 53127 Bonn, Germany.
3 Max Planck Institute for Biophysical Chemistry, Department of Structural Dynamics, 37077 Göttingen, Germany.
4 Institute of Innate Immunity, University of Bonn, 53127 Bonn, Germany.
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.
Keywords: ASC; Alzheimer’s disease; Aβ; NLRP3 inflammasome; microglia.