Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, India.
Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, India; National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Mohali 160062, Punjab, India.
Int J Biol Macromol. 2022 Apr 15;204:19-33. doi: 10.1016/j.ijbiomac.2022.01.172. Epub 2022 Feb 2.
Tauopathies such as Alzheimer's and Parkinson's diseases involve the abnormal deposition of tau aggregates in the brain and neuronal tissues. We report that a natural naphthoquinone, shikonin, impeded the oligomerization and fibrillization of tau. The compound strongly inhibited heparin, arachidonic acid, and RNA-induced tau aggregation. Atomic force microscopy, dynamic light scattering, SDS-PAGE, and dot blot assays revealed that shikonin diminished tau oligomerization and decreased the mean size of tau oligomers. Transmission electron microscopy and atomic force microscopy analysis further showed that shikonin could suppress tau fibrillization and shorten the tau filaments. Shikonin inhibited tau droplet formation. The compound significantly reduced the aggregation rate of a tryptophan mutant (Y310W-tau) of tau. In addition, shikonin disaggregated preformed tau filaments with a half-maximal disaggregation concentration (DC) of 6.3 ± 0.4 μM. Pre-treatment of neuroblastoma cells (SH-SY5Y) with shikonin protected the cells from the toxicity induced by tau oligomers and increased their viability. The findings imply that shikonin inhibited several steps in the tau aggregation pathways, especially the early stages, such as liquid-liquid phase separation. Therefore, shikonin is an attractive candidate for developing a therapy against tauopathy.
tau 病，如阿尔茨海默病和帕金森病，涉及 tau 聚集物在大脑和神经元组织中的异常沉积。我们报告称，一种天然萘醌化合物紫草素可阻止 tau 的寡聚化和纤维化。该化合物强烈抑制肝素、花生四烯酸和 RNA 诱导的 tau 聚集。原子力显微镜、动态光散射、SDS-PAGE 和斑点印迹分析表明，紫草素可减少 tau 寡聚化并降低 tau 寡聚物的平均大小。透射电子显微镜和原子力显微镜分析进一步表明，紫草素可以抑制 tau 纤维化并缩短 tau 纤维。紫草素抑制 tau 液滴形成。该化合物显著降低了 tau 色氨酸突变体（Y310W-tau）的聚集率。此外，紫草素可使预先形成的 tau 纤维解聚，半最大解聚浓度（DC）为 6.3±0.4 μM。紫草素预处理神经母细胞瘤细胞（SH-SY5Y）可保护细胞免受 tau 寡聚物诱导的毒性，并提高其存活率。这些发现表明，紫草素抑制 tau 聚集途径的多个步骤，特别是液-液相分离等早期阶段。因此，紫草素是开发 tau 病治疗方法的有吸引力的候选药物。
