Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Key Laboratory of Industrial Fermentation (Ministry of Education), Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, 430068, Wuhan, China.
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China.
Nat Commun. 2023 Sep 6;14(1):5444. doi: 10.1038/s41467-023-41241-6.
Preventing tau aggregation is a potential therapeutic strategy in Alzheimer's disease and other tauopathies. Recently, liquid-liquid phase separation has been found to facilitate the formation of pathogenic tau conformations and fibrillar aggregates, although many aspects of the conformational transitions of tau during the phase transition process remain unknown. Here, we demonstrate that the tau aggregation inhibitor methylene blue promotes tau liquid-liquid phase separation and accelerates the liquid-to-gel transition of tau droplets independent of the redox activity of methylene blue. We further show that methylene blue inhibits the conversion of tau droplets into fibrils and reduces the cytotoxicity of tau aggregates. Although gelation slows down the mobility of tau and tubulin, it does not impair microtubule assembly within tau droplets. These findings suggest that methylene blue inhibits tau amyloid fibrillization and accelerates tau droplet gelation via distinct mechanisms, thus providing insights into the activity of tau aggregation inhibitors in the context of phase transition.
抑制 tau 聚集是阿尔茨海默病和其他 tau 病的一种潜在治疗策略。最近发现液-液相分离有助于形成致病性 tau 构象和纤维状聚集物，尽管 tau 在相变过程中的构象转变的许多方面仍然未知。在这里，我们证明 tau 聚集抑制剂亚甲蓝促进 tau 液-液相分离，并加速 tau 液滴的液相到凝胶相转变，而不依赖于亚甲蓝的氧化还原活性。我们进一步表明，亚甲蓝抑制 tau 液滴转化为原纤维，并降低 tau 聚集物的细胞毒性。尽管凝胶化会降低 tau 和微管蛋白的流动性，但它不会损害 tau 液滴内的微管组装。这些发现表明，亚甲蓝通过不同的机制抑制 tau 淀粉样纤维形成并加速 tau 液滴凝胶化，从而为了解相变背景下 tau 聚集抑制剂的活性提供了线索。
