Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX, 77555, USA.
Departments of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, 77555, USA.
Sci Rep. 2019 Dec 12;9(1):19011. doi: 10.1038/s41598-019-55419-w.
The pathological aggregation and accumulation of tau, a microtubule-associated protein, is a common feature amongst more than 18 different neurodegenerative diseases that are collectively known as tauopathies. Recently, it has been demonstrated that the soluble and hydrophobic tau oligomers are highly toxic in vitro due to their capacity towards seeding tau misfolding, thereby propagating the tau pathology seen across different neurodegenerative diseases. Modulating the aggregation state of tau oligomers through the use of small molecules could be a useful therapeutic strategy to target their toxicity, regardless of other factors involved in their formation. In this study, we screened and tested a small library of newly synthesized curcumin derivatives against preformed recombinant tau oligomers. Our results show that the curcumin derivatives affect and modulate the tau oligomer aggregation pathways, converting to a more aggregated non-toxic state as assessed in the human neuroblastoma SH-SY5Y cell line and primary cortical neuron cultures. These results provide insight into tau aggregation and may become a basis for the discovery of new therapeutic agents, as well as advance the diagnostic field for the detection of toxic tau oligomers.
tau 是一种微管相关蛋白，其病理性聚集和积累是 18 种以上不同神经退行性疾病的共同特征，这些疾病统称为 tau 病。最近，已经证明可溶性和疏水性 tau 寡聚物在体外具有高度毒性，因为它们能够引发 tau 错误折叠，从而在不同的神经退行性疾病中传播 tau 病理学。通过使用小分子来调节 tau 寡聚物的聚集状态可能是一种有用的治疗策略，无论其形成涉及哪些其他因素，都可以靶向它们的毒性。在这项研究中，我们对新合成的姜黄素衍生物进行了筛选和测试，以对抗预先形成的重组 tau 寡聚物。我们的结果表明，姜黄素衍生物影响并调节 tau 寡聚物的聚集途径，如在人神经母细胞瘤 SH-SY5Y 细胞系和原代皮质神经元培养物中评估的那样，转化为更聚集但无毒的状态。这些结果提供了 tau 聚集的见解，并可能成为发现新治疗剂的基础，并推进用于检测有毒 tau 寡聚物的诊断领域。
