Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, Guangdong 518060, China; Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, Guangdong 518055, China.
Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, Guangdong 518060, China.
Int J Biol Macromol. 2021 May 1;178:381-393. doi: 10.1016/j.ijbiomac.2021.02.210. Epub 2021 Mar 1.
Alzheimer's disease is a neurodegenerative disease which severely impacts the health of the elderly. Current treatments are only able to alleviate symptoms, but not prevent or cure the disease. The neurofibrillary tangles formed by tau protein aggregation are one of the defining characteristics of Alzheimer's disease, so tau protein has become a key target for the drug design. In this study, we show that fisetin, a plant-derived polyphenol compound, can inhibit aggregation of the tau fragment, K18, and can disaggregate tau K18 filaments in vitro. Meanwhile it is able to prevent the formation of tau aggregates in cells. Both experimental and computational studies indicate that fisetin could directly interact with tau K18 protein. The binding is mainly created by hydrogen bond and van der Waal force, prevents the formation of β-strands at the two hexapeptide motifs, and does not perturb the secondary structure or the tubulin binding ability of tau protein. In summary, fisetin might be a candidate for further development as a potential preventive or therapeutic drug for Alzheimer's disease.
阿尔茨海默病是一种神经退行性疾病，严重影响老年人的健康。目前的治疗方法只能缓解症状，而不能预防或治愈这种疾病。由 tau 蛋白聚集形成的神经原纤维缠结是阿尔茨海默病的一个重要特征，因此 tau 蛋白已成为药物设计的关键靶点。在这项研究中，我们表明，根皮素，一种植物来源的多酚化合物，可以抑制 tau 片段 K18 的聚集，并可以在体外解聚 tau K18 纤维。同时，它还能够防止细胞中 tau 聚集的形成。实验和计算研究均表明，根皮素可以直接与 tau K18 蛋白相互作用。这种结合主要是通过氢键和范德华力形成的，可以防止两个六肽基序处β-折叠的形成，并且不会干扰 tau 蛋白的二级结构或微管结合能力。总之，根皮素可能是进一步开发为预防或治疗阿尔茨海默病的潜在药物的候选物。
