Yuan Xueling, Wang Zhuo, Zhang Lei, Sui Rubo, Khan Suliman
Department of Neurology, the First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121099, China.
School of Nursing, Jinzhou Medical University, Jinzhou 121099, China.
Int J Biol Macromol. 2021 Jul 31;183:1184-1190. doi: 10.1016/j.ijbiomac.2021.05.041. Epub 2021 May 6.
Aggregation of tau protein into the form of insoluble amyloid fibrils is linked with Alzheimer's disease. The identification of potential small molecules that can inhibit tau protein from undergoing aggregation has received a great deal of interest, recently. In the present study, the possible inhibitory effects of liquiritigenin as a member of chiral flavanone family on tau amyloid fibrils formation and their resulting neurotoxicity were assessed by different biophysical and cellular assays. The inhibitory effect of the liquiritigenin against tau amyloid formation was investigated using thioflavin T (ThT) and 1-Anilino-8-naphthalene sulfonate (ANS) fluorescence spectroscopy, Congo red (CR) binding assays, transmission electron microscopy (TEM) analysis, and circular dichroism (CD) spectroscopy. Neurotoxicity assays were also performed against neuron-like cells (SH-SY5Y) using 3-(4,5-Dimethylthiazol)-2,5-diphenyltetrazolium bromide (MTT) reduction, reactive oxygen species (ROS), catalase (CAT) and caspase-3 activity measurements. We found that liquiritigenin served as an efficient inhibitor of tau amyloid fibrils formation through prevention of structural transition in tau structure, exposure of hydrophobic patches and their associated neurotoxicity mediated by decrease in the production of ROS and caspase-3 activity and elevation of CAT activity. These data may finally find applications in the development of promising inhibitors against amyloid fibril formation and treatment of Alzheimer's disease.
tau蛋白聚集成不溶性淀粉样原纤维的形式与阿尔茨海默病有关。最近，能够抑制tau蛋白聚集的潜在小分子的鉴定受到了广泛关注。在本研究中，通过不同的生物物理和细胞试验评估了作为手性黄烷酮家族成员的甘草素对tau淀粉样原纤维形成及其导致的神经毒性的可能抑制作用。使用硫黄素T（ThT）和1-苯胺基-8-萘磺酸盐（ANS）荧光光谱、刚果红（CR）结合试验、透射电子显微镜（TEM）分析和圆二色性（CD）光谱研究了甘草素对tau淀粉样蛋白形成的抑制作用。还使用3-（4,5-二甲基噻唑）-2,5-二苯基四氮唑溴盐（MTT）还原、活性氧（ROS）、过氧化氢酶（CAT）和半胱天冬酶-3活性测量对神经元样细胞（SH-SY5Y）进行了神经毒性试验。我们发现，甘草素通过防止tau结构的结构转变、疏水性斑块的暴露及其相关的神经毒性（通过降低ROS的产生和半胱天冬酶-3活性以及提高CAT活性介导），成为tau淀粉样原纤维形成的有效抑制剂。这些数据最终可能在开发有前景的抗淀粉样原纤维形成抑制剂和治疗阿尔茨海默病方面找到应用。
