Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder affecting millions of people worldwide. Therefore, finding effective interventions and therapies is extremely important. AD is one of over 20 different disorders known as tauopathies, characterized by the pathological aggregation and accumulation of tau, a microtubule-associated protein. Tau aggregates are heterogeneous and can be divided into two major groups: large metastable fibrils, including neurofibrillary tangles, and oligomers. The smaller, soluble and dynamic tau oligomers have been shown to be more toxic with more proficient seeding properties for the propagation of tau pathology as compared to the fibrillar Paired Helical Filaments (PHFs). Therefore, developing small molecules that target and interact with toxic tau oligomers can be beneficial to modulate their aggregation pathways and toxicity, preventing progression of the pathology. In this study, we show that Azure C (AC) is capable of modulating tau oligomer aggregation pathways at micromolar concentrations and rescues tau oligomers-induced toxicity in cell culture. We used both biochemical and biophysical in vitro techniques to characterize preformed tau oligomers in the presence and absence of AC. Interestingly, AC prevents toxicity not by disassembling the oligomers but rather by converting them into clusters of aggregates with nontoxic conformation.

中文翻译：

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Azure C靶向并调节有毒的Tau低聚物

阿尔茨海默氏病（AD）是最常见的与年龄相关的神经退行性疾病，影响着全球数百万人。因此，找到有效的干预措施和疗法极为重要。AD是被称为tauopathies的20多种不同疾病之一，其特征在于tau（一种微管相关蛋白）的病理性聚集和积累。Tau聚集体是异质的，可以分为两大类：包括神经原纤维缠结的大亚稳原纤维和低聚物。与原纤维成对的螺旋长丝（PHF）相比，较小的，可溶的和动态的tau低聚物显示出更大的毒性，并具有更有效的tau病理传播播种特性。所以，研发靶向有毒tau寡聚体并与之相互作用的小分子可能对调节其聚集途径和毒性，防止病理进展很有帮助。在这项研究中，我们表明Azure C（AC）能够以微摩尔浓度调节tau低聚物聚集途径，并拯救tau低聚物在细胞培养中诱导的毒性。我们使用生化和生物物理体外技术在存在和不存在AC的情况下表征预制的tau寡聚物。有趣的是，AC不会通过分解低聚物来防止毒性，而是通过将它们转变为具有无毒构象的聚集体簇来防止。我们表明，Azure C（AC）能够以微摩尔浓度调节tau低聚物聚集途径，并在细胞培养中拯救tau低聚物诱导的毒性。我们使用生化和生物物理体外技术在存在和不存在AC的情况下表征预制的tau寡聚物。有趣的是，AC不会通过分解低聚物来防止毒性，而是通过将它们转变为具有无毒构象的聚集体簇来防止。我们表明，Azure C（AC）能够以微摩尔浓度调节tau低聚物聚集途径，并在细胞培养中拯救tau低聚物诱导的毒性。我们使用生化和生物物理体外技术在存在和不存在AC的情况下表征预制的tau寡聚物。有趣的是，AC不会通过分解低聚物来防止毒性，而是通过将它们转变为具有无毒构象的聚集体簇来防止。