Abstract：
A prominent characteristic of Alzheimer\'s disease (AD) is the deposition of both amyloid-β (Aβ) peptide and tau protein in the brain. Aβ and tau not only induce toxicity through self-aggregation but also induce more potent toxicity through the synergistic action of Aβ and tau. In particular, neurotoxic aggregates of Aβ and tau directly affect several AD pathologies including neuroinflammation and cognitive decline. Therefore, there is increasing interest in strategies to modulate the aggregation and dissociation of Aβ and tau for treatment of AD. Our recent study found that Uncaria rhynchophylla (UR) has a therapeutic effect on AD via the inhibition of Aβ aggregation and attenuating Aβ-mediated pathogenesis of AD. However, no studies have investigated whether UR has anti- and disaggregation effects on both Aβ and tau. In this study, we showed the significant effects of UR on aggregation and dissociation of Aβ42 and tau K18 using a thioflavin T (ThT) assay. In addition, histological study revealed an inhibitory effect of UR on the accumulation of Aβ and tau and AD-related pathologies in 3xTg mice with both Aβ and tau pathology. Furthermore, we found that rhynchophylline and corynoxeine, bioactive components of UR, could modulate the aggregation and dissociation of both Aβ and tau using molecular docking simulation, isothermal titration calorimetry, and ThT assays. In conclusion, our results demonstrate that UR can inhibit the aggregation of Aβ and tau and promote the degradation of their aggregates in AD.
摘要：
阿尔茨海默病（AD）的一个突出特征是淀粉样β（Aβ）肽和tau蛋白在大脑中的沉积。Aβ和tau不仅通过自聚集诱导毒性,而且通过Aβ和tau的协同作用诱导更有效的毒性。特别是,Aβ和tau的神经毒性聚集体直接影响几种AD病理，包括神经炎症和认知功能下降。因此,人们对调节Aβ和tau的聚集和解离以治疗AD的策略越来越感兴趣。我们最近的研究发现钩藤属（UR）通过抑制Aβ聚集和减轻Aβ介导的AD发病机制对AD具有治疗作用。然而,没有研究调查UR是否对Aβ和tau具有抗和解聚作用。在这项研究中,我们使用硫黄素T（ThT）测定法显示了UR对Aβ42和tauK18的聚集和解离的显着影响。此外,组织学研究显示，UR对具有Aβ和tau病理的3xTg小鼠中Aβ和tau的积累以及AD相关病理的抑制作用。此外，我们发现钩藤碱和山茱萸碱,UR的生物活性成分，使用分子对接模拟可以调节Aβ和tau的聚集和解离，等温滴定量热法，和ThT测定。总之,我们的结果表明，UR可以抑制Aβ和tau的聚集，并促进其聚集体在AD中的降解。
