ß-Amyloid Clustering around ASC Fibrils Boosts Its Toxicity in Microglia.

ABSTRACT

Alzheimer's disease is the world's most common neurodegenerative disorder. It is associated with neuroinflammation involving activation of microglia by ß-amyloid (Aß) deposits. Based on previous studies showing apoptosis-associated speck-like protein containing a CARD (ASC) binding and cross-seeding extracellular Aß, we investigate the propagation of ASC between primary microglia and the effects of ASC-Aß 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-Aß 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 Aß by microglia. Together, these data enable a closer look at the turning point from acute to chronic Aß-related neuroinflammation through formation of ASC-Aß composites.