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[200402 Àú³Î ¹ßÇ¥] ¥â-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

¥â-Amyloid Clustering around ASC Fibrils Boosts Its Toxicity in Microglia

Highlights

  • Exogenous ASC can be incorporated by the NLRP3 inflammasome of the recipient microglia
  • A¥â binding to ASC fibrils amplifies NLRP3 inflammasome activity
  • Microglia exposed to ASC-A¥â composites undergo pyroptotic cell death
  • Intra- and extracellular ASC-A¥â binding impairs A¥â 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 ¥â-amyloid (A¥â) deposits. Based on previous studies showing apoptosis-associated speck-like protein containing a CARD (ASC) binding and cross-seeding extracellular A¥â, we investigate the propagation of ASC between primary microglia and the effects of ASC-A¥â 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-A¥â 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 A¥â by microglia. Together, these data enable a closer look at the turning point from acute to chronic A¥â-related neuroinflammation through formation of ASC-A¥â composites.



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