The formation of amyloid β-protein (1-42) (Aβ42) oligomers and Aβ42 oligomer cytotoxicity are two defining characteristics of the etiology of Alzheimer's disease (AD). In this study, we found that matrine (Mat) could maintain or even enhance the cytotrophic effect of Aβ42 monomers by inhibiting their aggregation and by working in a manner similar to synergy with Aβ42 monomers. Moreover, Mat could also exert a cytoprotective effect by actively promoting the disaggregation of immature Aβ42 oligomers in a concentration-dependent manner. Although Mat at intermediate concentrations (1-50 μM) exhibited both cytotrophic and cytoprotective effects on SH-SY5Y cells, Mat at higher concentrations (100 μM) only exhibited a cytoprotective effect. Molecular docking studies reveal that these differences are a result of the different interactions between Mat and Aβ42 oligomers that occur at different molecular ratios. Our results support the hypothesis that there may be a Mat-like metabolite in the human brain that acts as a molecular chaperone for Aβ42 monomers. A deficiency in this chaperone would result in the gradual aggregation of Aβ42 monomers, and eventually, formation of toxic Aβ42 oligomers. In addition, reduction or clearance of Aβ42 aggregates or deposits and inhibition or elimination of the toxicity of oligomeric Aβ42, were not always directly correlated. Finally, the site(s) responsible for cytotoxicity in Aβ42 oligomers may be located in the integrated region of the N-terminal fragments of Aβ42 chains. This study provides valuable insights into the mechanisms involved in the development of natural drugs for the treatment of Alzheimer's disease.

中文翻译：

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苦参碱对寡聚淀粉样β蛋白的细胞毒性的非线性和混合抑制作用。

淀粉样β蛋白（1-42）（Aβ42）寡聚物的形成和Aβ42寡聚物的细胞毒性是阿尔茨海默氏病（AD）的病因学的两个定义特征。在这项研究中，我们发现苦参碱（Mat）可以通过抑制Aβ42单体的聚集并通过类似于与Aβ42单体的协同作用来维持甚至增强Aβ42单体的细胞营养作用。此外，Mat还可以通过以浓度依赖的方式积极促进未成熟的Aβ42低聚物的解离而发挥细胞保护作用。尽管中等浓度（1-50μM）的Mat对SH-SY5Y细胞既表现出细胞营养作用，又表现出细胞保护作用，但较高浓度（100μM）的Mat仅表现出细胞保护作用。分子对接研究表明，这些差异是由于Mat与Aβ42低聚物之间以不同的分子比发生的不同相互作用所致。我们的结果支持以下假设：人脑中可能存在类似于Mat的代谢物，可作为Aβ42单体的分子伴侣。该分子伴侣的缺乏将导致Aβ42单体逐渐聚集，并最终形成有毒的Aβ42低聚物。另外，Aβ42聚集体或沉积物的减少或清除以及寡聚Aβ42的毒性的抑制或消除并不总是直接相关的。最后，负责Aβ42寡聚体的细胞毒性的位点可以位于Aβ42链的N末端片段的整合区域。