2024年第51卷第3期目录
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封面故事:阿尔茨海默病(AD) 是一种中枢神经系统退行性疾病,主要病理特征之一是β淀粉样
蛋白(Aβ) 在大脑内的异常聚集。Aβ的异常聚集体具有神经毒性,是导致神经元损伤的罪魁祸
首。研究表明转甲状腺素蛋白(TTR) 能够延缓AD的发病进程,对AD具有神经保护作用,TTR的
这种神经保护作用主要体现在其能够抑制Aβ毒性聚集体的形成。该研究结果表明TTR可通过两种
方式抑制Aβ毒性聚集体的形成:一方面TTR四聚体和单体能够与Aβ单体结合,抑制Aβ聚集;另一
方面TTR单体能够与Aβ聚集体形成聚合度更高的低毒或无毒共聚体。该研究揭示了TTR对AD的神
经保护作用机制,为AD的治疗提供了新的线索。
(周双艳,黄垚心,李鑫,白佳慧,袁帅. 转甲状腺素蛋白抑制β 淀粉样蛋白聚集的分子机制研究,
本期第633~646 页)
Cover Story:Objective It was reported that the transthyretin (TTR) has a neuroprotective effect on Alzheimer’s disease (AD), which is manifested by the ability of TTR to inhibit the pathological aggregation of amyloid beta protein (Aβ). In this work, we investigated the mechanism of the interactions between TTR and Aβ at the molecular level to reveal the neuroprotective effect of TTR on AD.Methods Protein-protein docking was used to explore the models of interaction between different structural forms of TTR and Aβ, and molecular dynamics simulation was further applied to investigate the dynamic process of the interaction between the two.Results Both TTR tetramer and monomer can interact with Aβ monomer, and the thyroxine-binding channel of TTR tetramer is the main binding site of Aβ monomer. In addition, the EF helix and EF loop of TTR tetramer were also able to bind Aβ monomer. When the TTR tetramer dissociates, the hydrophobic site of the internal TTR monomer is exposed, which has a strong affinity for Aβ monomer. For the interaction between Aβ aggregates and TTR, a higher degree of aggregation can be formed between TTR monomer and Aβ aggregates due to the β-sheet-rich property of TTR monomer and Aβ aggregates, which may therefore reduce the cytotoxicity of Aβ aggregates.Conclusion Both TTR tetramer and monomer can inhibit Aβ aggregation by “sequestering” Aβ monomer, while TTR monomer can reduce the cytotoxicity of Aβ aggregates by forming large co-aggregation with Aβ aggregates. This work can provide an important theoretical basis for the design and discovery of anti-AD drugs based on the neuroprotective effects of TTR.
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综述与专论
研究报告
技术与方法
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