Department of Neurodegenerative Disease and Gerontopsychiatry/Neurology, University of Bonn Medical Center, 53127 Bonn, Germany.
Institute of Structural Biology, University of Bonn, 53127 Bonn, Germany.
Cell Rep. 2020 Mar 17;30(11):3743-3754.e6. doi: 10.1016/j.celrep.2020.02.025.
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.
阿尔茨海默病是世界上最常见的神经退行性疾病。它与神经炎症有关，涉及β-淀粉样蛋白（Aβ）沉积激活小胶质细胞。基于先前的研究表明凋亡相关斑点样蛋白包含一个 CARD（ASC）结合和交叉播种细胞外 Aβ，我们研究 ASC 在原代小胶质细胞之间的传播以及 ASC-Aβ 复合物对小胶质细胞炎症小体和功能的影响。事实上，由细胞焦亡释放的 ASC 可以在功能上整合到相邻的小胶质细胞 NOD 样受体蛋白（NLRP3）炎症小体中。与仅蛋白质应用相比，暴露于 ASC-Aβ 复合物会放大促炎反应，导致细胞焦亡死亡，释放功能正常的 ASC，并诱导正反馈刺激恶性循环。围绕 ASC 纤维的聚集也会损害小胶质细胞对 Aβ 的清除。总之，这些数据使我们能够更深入地了解通过形成 ASC-Aβ 复合物，从急性到慢性 Aβ 相关神经炎症的转折点。
