Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, India.
J Alzheimers Dis. 2017;60(3):999-1014. doi: 10.3233/JAD-170351.
The pathological aggregation of tau is a common feature of most of the neuronal disorders including frontotemporal dementia, Parkinson's disease, and Alzheimer's disease. The inhibition of tau aggregation is considered to be one of the important strategies for treating these neurodegenerative diseases. Curcumin, a natural polyphenolic molecule, has been reported to have neuroprotective ability. In this work, curcumin was found to bind to adult tau and fetal tau with a dissociation constant of 3.3±0.4 and 8±1 μM, respectively. Molecular docking studies indicated a putative binding site of curcumin in the microtubule-binding region of tau. Using several complementary techniques, including dynamic light scattering, thioflavin S fluorescence, 90° light scattering, electron microscopy, and atomic force microscopy, curcumin was found to inhibit the aggregation of tau. The dynamic light scattering analysis and atomic force microscopic images revealed that curcumin inhibits the oligomerization of tau. Curcumin also disintegrated preformed tau oligomers. Using Far-UV circular dichroism, curcumin was found to inhibit the β-sheets formation in tau indicating that curcumin inhibits an initial step of tau aggregation. In addition, curcumin inhibited tau fibril formation. Furthermore, the effect of curcumin on the preformed tau filaments was analyzed by atomic force microscopy, transmission electron microscopy, and 90° light scattering. Curcumin treatment disintegrated preformed tau filaments. The results indicated that curcumin inhibited the oligomerization of tau and could disaggregate tau filaments.
tau 蛋白的病理性聚集是包括额颞叶痴呆、帕金森病和阿尔茨海默病在内的大多数神经元疾病的共同特征。抑制 tau 聚集被认为是治疗这些神经退行性疾病的重要策略之一。姜黄素是一种天然多酚分子，已被报道具有神经保护能力。在这项工作中，发现姜黄素与成人 tau 和胎牛 tau 的解离常数分别为 3.3±0.4 和 8±1 μM。分子对接研究表明姜黄素在 tau 的微管结合区域有一个潜在的结合位点。使用几种互补技术，包括动态光散射、硫黄素 S 荧光、90°光散射、电子显微镜和原子力显微镜，发现姜黄素抑制 tau 的聚集。动态光散射分析和原子力显微镜图像显示姜黄素抑制 tau 的寡聚化。姜黄素还可分解已形成的 tau 寡聚物。使用 Far-UV 圆二色性，发现姜黄素抑制 tau 中β-折叠的形成，表明姜黄素抑制 tau 聚集的初始步骤。此外，姜黄素抑制 tau 原纤维的形成。此外，还通过原子力显微镜、透射电子显微镜和 90°光散射分析了姜黄素对已形成的 tau 原纤维的影响。姜黄素处理可使已形成的 tau 原纤维解体。结果表明，姜黄素抑制 tau 的寡聚化，并能解聚 tau 原纤维。
