Abstract：
Amyloid-beta (Aβ42) aggregates are characteristic Alzheimer\'s disease signatures, but probing how their nanoscale architectures influence their growth and decay remains challenging using current technologies. Here, we apply time-lapse single-molecule orientation-localization microscopy (SMOLM) to measure the orientations and rotational \"wobble\" of Nile blue (NB) molecules transiently binding to Aβ42 fibrils. We correlate fibril architectures measured by SMOLM with their growth and decay over the course of 5 to 20 min visualized by single-molecule localization microscopy (SMLM). We discover that stable Aβ42 fibrils tend to be well-ordered and signified by well-aligned NB orientations and small wobble. SMOLM also shows that increasing order and disorder are signatures of growing and decaying fibrils, respectively. We also observe SMLM-invisible fibril remodeling, including steady growth and decay patterns that conserve β-sheet organization. SMOLM reveals that increased fibril architectural heterogeneity is correlated with dynamic remodeling and that large-scale fibril remodeling tends to originate from strongly heterogeneous local regions.
摘要：
淀粉样β（Aβ42）聚集体是阿尔茨海默病的特征性特征，但是探索它们的纳米级结构如何影响它们的生长和衰变仍然具有挑战性，使用当前的技术。这里,我们应用延时单分子取向定位显微镜(SMOLM)测量瞬时结合Aβ42原纤维的尼罗兰(NB)分子的取向和旋转“摆动”。我们将SMOLM测量的原纤维结构与单分子定位显微镜（SMLM）可视化的5至20分钟内的生长和衰变相关联。我们发现，稳定的Aβ42原纤维往往是有序的，并通过对齐的NB方向和小的摆动来表示。SMOLM还显示，增加的顺序和无序是生长和腐烂的原纤维的特征，分别。我们还观察到SMLM-隐形原纤维重塑，包括保护β-sheet组织的稳定增长和衰变模式。SMOLM揭示了增加的原纤维结构异质性与动态重塑相关，并且大规模的原纤维重塑往往源于强烈的异质局部区域。
