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[200402 저널 발표] β-Amyloid Clustering around ASC Fibrils Boosts Its Toxicity in Microglia

Kyujin Suh │ 2020-04-01

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https://www.cell.com/cell-reports/fulltext/S2211-1247(20)30186-8


ARTICLE| VOLUME 30, ISSUE 11P3743-3754.E6, MARCH 17, 2020

β-Amyloid Clustering around ASC Fibrils Boosts Its Toxicity in Microglia

Highlights

  • 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

Summary

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.



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