β-Amyloid Clustering around ASC Fibrils Boosts Its Toxicity in Microglia
Exogenous ASC can be incorporated by the NLRP3 inflammasome of the recipient microglia
Aβ binding to ASC fibrils amplifies NLRP3 inflammasome activity
Microglia exposed to ASC-Aβ composites undergo pyroptotic cell death
Intra- and extracellular ASC-Aβ binding impairs Aβ clearance by microglia
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.