Tang Jiaxing, Feng Dushuo, Wang Feng, Guan Lulu, Xu Zhengdong, Zou Yu
School of Physical Education, Xiangnan University, 889 Chenzhou Avenue, Chenzhou 423000, People's Republic of China.
Department of Sport and Exercise Science, College of Education, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, Zhejiang, People's Republic of China.
Phys Chem Chem Phys. 2025 Jun 25;27(25):13714-13726. doi: 10.1039/d5cp01420d.
The aggregation of hyperphosphorylated tau protein into neurofibrillary tangles (NFTs) is associated with Alzheimer's disease (AD). Inhibiting tau aggregation or disrupting preformed fibrillar aggregates may be legitimate therapeutic approaches for AD. Epinephrine, also known as adrenaline, is an endogenous small molecule secreted by the adrenal medulla and can be stimulated by resistance exercise. It was proved to inhibit tau aggregation . However, atomic insights into the influence of EP on the AD-related tau remain largely unclear. In this work, we performed all-atom molecular dynamics (MD) simulations on the R3-R4 (the third and fourth repeat) tau protofibril and fibril associated with AD, without and with EP molecules. The results reveal that EP can increase the structural instability and flexibility of the R3-R4 protofibril, and elicit a β-sheet-to-coil transformation and loosely-packed conformation. More importantly, EP remodels the K353-D358 salt-bridges that play a vital role in stabilizing the protofibril configuration. Binding analysis determines that EP binds with the protofibril preferentially through hydrophobic, hydrogen-bonding (H-bonding), π-π stacking and cation-π interactions. On the other hand, EP destabilizes and may reverse a liquid-to-solid phase transition (LSPT) of the AD-related tau fibril. The binding modes of EP with the fibrils exhibit differences to those with the protofibrils. By disclosing these findings, our work provides helpful clues for drug candidate design and exercise therapy for treating AD.
过度磷酸化的tau蛋白聚集成神经原纤维缠结（NFTs）与阿尔茨海默病（AD）相关。抑制tau蛋白聚集或破坏预先形成的纤维状聚集体可能是治疗AD的合理方法。肾上腺素，也被称为肾上腺激素，是肾上腺髓质分泌的一种内源性小分子，可通过抗阻运动刺激产生。已证明它能抑制tau蛋白聚集。然而，关于肾上腺素（EP）对AD相关tau蛋白影响的原子层面见解在很大程度上仍不清楚。在这项工作中，我们对与AD相关的R3 - R4（第三和第四重复序列）tau原纤维和纤维进行了全原子分子动力学（MD）模拟，模拟过程中有无EP分子存在。结果表明，EP可增加R3 - R4原纤维的结构不稳定性和灵活性，并引发β - 折叠到卷曲的转变以及松散堆积的构象。更重要的是，EP重塑了在稳定原纤维构型中起关键作用的K353 - D358盐桥。结合分析确定，EP与原纤维优先通过疏水、氢键（H键）、π - π堆积和阳离子 - π相互作用结合。另一方面，EP使AD相关tau纤维的液 - 固相变（LSPT）不稳定，并可能使其逆转。EP与纤维的结合模式与原纤维有所不同。通过揭示这些发现，我们的工作为治疗AD的候选药物设计和运动疗法提供了有益线索。
