The aggregation of amyloid-β (Aβ) into oligomers and fibrillary structures is critical for the pathogenesis of Alzheimer's disease (AD). Recently, research effort has been focused on developing novel agents that can preferentially suppress Aβ oligomer mediated toxicities, for example, by directly targeting these toxic assemblies. The compound RD2 has been developed and optimized for Aβ42 monomer binding and stabilization of the monomer in its native intrinsically disordered conformation. It has been demonstrated to improve and even reverse the cognitive and behavioral deficits in AD mouse models, while the detailed mechanism of action is not fully clarified. Here we focused on exploring the interaction between RD2 and Aβ42 monomers and its consequences for the fibrillation of Aβ42. RD2 binds to Aβ42 monomers with nanomolar affinities, according to microscale thermophoresis and surface plasmon resonance measurements. Complexes between RD2 and Aβ42 monomers are formed at 1:1 and other stoichiometries, as revealed by analytical ultracentrifugation. At substoichiometric levels, RD2 slows down the secondary structure conversion of Aβ42 and significantly delays the fibril formation. Our research provides experimental evidence in supporting that RD2 eliminates toxic Aβ assemblies by stabilizing Aβ monomers in their native intrinsically disordered conformation. The study further supports the promising application of RD2 in counteracting Aβ aggregation related pathologies.

中文翻译：

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迈向临床阶段全α-对映体肽RD2对Aβ42聚集的作用方式。

淀粉样β（Aβ）聚集成寡聚物和原纤维结构对于阿尔茨海默氏病（AD）的发病机理至关重要。近来，研究工作已集中在开发可以优先抑制Aβ寡聚物介导的毒性的新型试剂上，例如，通过直接靶向这些毒性装配。已经开发并优化了化合物RD2，用于Aβ42单体的结合和单体在其天然固有无序构象中的稳定化。它已被证明可以改善甚至逆转AD小鼠模型中的认知和行为缺陷，而其详细的作用机理尚未完全阐明。在这里，我们重点研究RD2和Aβ42单体之间的相互作用及其对Aβ42的原纤化的影响。RD2以纳摩尔亲和力与Aβ42单体结合，根据微尺度热泳和表面等离振子共振测量。分析超速离心显示，RD2和Aβ42单体之间的络合物以1：1和其他化学计量比形成。在亚化学计量水平，RD2减慢了Aβ42的二级结构转化，并显着延迟了原纤维形成。我们的研究为支持RD2通过稳定Aβ单体的天然内在无序构象消除了有毒的Aβ装配体提供了实验证据。这项研究进一步支持了RD2在对抗Aβ聚集相关病理方面的有希望的应用。在亚化学计量水平，RD2减慢了Aβ42的二级结构转化，并显着延迟了原纤维形成。我们的研究为支持RD2通过稳定Aβ单体的天然内在无序构象消除了有毒的Aβ装配体提供了实验证据。这项研究进一步支持了RD2在对抗Aβ聚集相关病理方面的有希望的应用。在亚化学计量水平，RD2减慢了Aβ42的二级结构转化，并显着延迟了原纤维形成。我们的研究为支持RD2通过稳定Aβ单体的天然内在无序构象消除了有毒的Aβ装配体提供了实验证据。这项研究进一步支持了RD2在对抗Aβ聚集相关病理方面的有希望的应用。