The mechanism of amyloid co-aggregation and its nucleation process are not fully understood in spite of extensive studies. Deciphering the interactions between proinflammatory S100A9 protein and Aβ₄₂ peptide in Alzheimer's disease is fundamental since inflammation plays a central role in the disease onset. Here we use innovative charge detection mass spectrometry (CDMS) together with biophysical techniques to provide mechanistic insight into the co-aggregation process and differentiate amyloid complexes at a single particle level. Combination of mass and charge distributions of amyloids together with reconstruction of the differences between them and detailed microscopy reveals that co-aggregation involves templating of S100A9 fibrils on the surface of Aβ₄₂ amyloids. Kinetic analysis further corroborates that the surfaces available for the Aβ₄₂ secondary nucleation are diminished due to the coating by S100A9 amyloids, while the binding of S100A9 to Aβ₄₂ fibrils is validated by a microfuidic assay. We demonstrate that synergy between CDMS, microscopy, kinetic and microfluidic analyses opens new directions in interdisciplinary research.

中文翻译：

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通过电荷检测质谱，显微镜，动力学和微流体分析揭示Aβ纤维表面上的S100A9淀粉样蛋白

尽管进行了广泛的研究，淀粉样蛋白共聚集的机制及其成核过程仍未完全了解。阐明促炎性S100A9蛋白与_Aβ42肽之间在阿尔茨海默氏病中的相互作用至关重要，因为炎症在疾病发作中起着核心作用。在这里，我们使用创新的电荷检测质谱（CDMS）以及生物物理技术来提供对共聚集过程的机械洞察力，并在单个粒子水平上区分淀粉样蛋白复合物。淀粉样蛋白的质量和电荷分布的组合，以及它们之间的差异的重建和详细的显微镜检查表明，共聚集涉及在_Aβ42表面上对S100A9原纤维进行模板化淀粉样蛋白。动力学分析进一步证实，由于S100A9淀粉样蛋白的包被，可用于_Aβ42二次成核的表面减少了，而通过微流体测定法验证了S100A9与_Aβ42的原纤维的结合。我们证明CDMS，显微镜，动力学和微流体分析之间的协同作用为跨学科研究开辟了新的方向。