PDF(Pubmed)
Abstract：
Intracellular tau fibrils are sources of neurotoxicity and oxidative stress in Alzheimer\'s. Current drug discovery efforts have focused on molecules with tau fibril disaggregation and antioxidation functions. However, recent studies suggest that membrane-bound tau-containing oligomers (mTCOs), smaller and less ordered than tau fibrils, are neurotoxic in the early stage of Alzheimer\'s. Whether tau fibril-targeting molecules are effective against mTCOs is unknown. The binding of epigallocatechin-3-gallate (EGCG), CNS-11, and BHT-CNS-11 to in silico mTCOs and experimental tau fibrils was investigated using machine learning-enhanced docking and molecular dynamics simulations. EGCG and CNS-11 have tau fibril disaggregation functions, while the proposed BHT-CNS-11 has potential tau fibril disaggregation and antioxidation functions like EGCG. Our results suggest that the three molecules studied may also bind to mTCOs. The predicted binding probability of EGCG to mTCOs increases with the protein aggregate size. In contrast, the predicted probability of CNS-11 and BHT-CNS-11 binding to the dimeric mTCOs is higher than binding to the tetrameric mTCOs for the homo tau but not for the hetero tau-amylin oligomers. Our results also support the idea that anionic lipids may promote the binding of molecules to mTCOs. We conclude that tau fibril-disaggregating and antioxidating molecules may bind to mTCOs, and that mTCOs may also be useful targets for Alzheimer\'s drug design.
摘要：
细胞内tau原纤维是阿尔茨海默病神经毒性和氧化应激的来源。目前的药物发现努力集中在具有tau原纤维解聚和抗氧化功能的分子上。然而,最近的研究表明，含有膜结合tau的寡聚物（mTCOs），比tau原纤维更小，更不有序，在阿尔茨海默氏症的早期阶段有神经毒性。Tau原纤维靶向分子是否对mTCOs有效尚不清楚。表没食子儿茶素-3-没食子酸酯（EGCG）的结合，使用机器学习增强的对接和分子动力学模拟研究了CNS-11和BHT-CNS-11对计算机mTCO和实验tau原纤维的影响。EGCG和CNS-11具有tau原纤维解聚功能，而提出的BHT-CNS-11具有潜在的tau原纤维解聚和抗氧化功能，如EGCG。我们的结果表明，所研究的三种分子也可能与mTCOs结合。EGCG与mTCO的预测结合概率随蛋白质聚集体大小而增加。相比之下,CNS-11和BHT-CNS-11与二聚体mTCOs结合的预测概率高于高tau与四聚体mTCOs结合的概率,而非异源tau-胰淀素寡聚体。我们的结果也支持阴离子脂质可以促进分子与mTCO的结合的观点。我们得出结论，tau原纤维解聚和抗氧化分子可能与mTCOs结合，mTCOs也可能是阿尔茨海默病药物设计的有用靶标。
