Experimental Pathology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping 581 83, Sweden.
Division of Molecular Biotechnology, Department of Physics, Chemistry and Biology, Linköping University, Linköping 581 83, Sweden.
Biochemistry. 2021 Sep 21;60(37):2773-2780. doi: 10.1021/acs.biochem.1c00265. Epub 2021 Sep 1.
The prevailing opinion is that prefibrillar β-amyloid (Aβ) species, rather than end-stage amyloid fibrils, cause neuronal dysfunction in Alzheimer's disease, although the mechanisms behind Aβ neurotoxicity remain to be elucidated. Luminescent conjugated oligothiophenes (LCOs) exhibit spectral properties upon binding to amyloid proteins and have previously been reported to change the toxicity of Aβ and prion protein. In a previous study, we showed that an LCO, pentamer formyl thiophene acetic acid (p-FTAA), changed the toxicity of Aβ. Here we investigated whether an LCO, heptamer formyl thiophene acetic acid (h-FTAA), could change the toxicity of Aβ by comparing its behavior with that of p-FTAA. Moreover, we investigated the effects on toxicity when Aβ with the Arctic mutation (Aβ) was aggregated with both LCOs. Cell viability assays on SH-SY5Y neuroblastoma cells demonstrated that h-FTAA has a stronger impact on Aβ toxicity than does p-FTAA. Interestingly, h-FTAA, but not p-FTAA, rescued the Aβ-mediated toxicity. Aggregation kinetics and binding assay experiments with Aβ and Aβ when aggregated with both LCOs showed that h-FTAA and p-FTAA either interact with different species or affect the aggregation in different ways. In conclusion, h-FTAA protects against Aβ and Aβ toxicity, thus showing h-FTAA to be a useful tool for improving our understanding of the process of Aβ aggregation linked to cytotoxicity.
普遍观点认为，在阿尔茨海默病中，引起神经元功能障碍的是原纤维前β-淀粉样蛋白（Aβ），而不是终末淀粉样纤维，尽管 Aβ 神经毒性的机制仍有待阐明。发荧光的共轭寡聚噻吩（LCO）在与淀粉样蛋白结合时表现出光谱特性，并且先前已报道其改变 Aβ 和朊病毒蛋白的毒性。在之前的研究中，我们表明 LCO，五聚体甲酰基噻吩乙酸（p-FTAA）改变了 Aβ 的毒性。在这里，我们通过比较其与 p-FTAA 的行为，研究了 LCO，七聚体甲酰基噻吩乙酸（h-FTAA）是否可以改变 Aβ 的毒性。此外，我们研究了当与两种 LCO 聚集的具有北极突变（Aβ）的 Aβ 时，对毒性的影响。在 SH-SY5Y 神经母细胞瘤细胞上进行的细胞活力测定表明，h-FTAA对 Aβ毒性的影响比 p-FTAA更强。有趣的是，h-FTAA，而不是 p-FTAA，挽救了 Aβ介导的毒性。与 Aβ 和与两种 LCO 聚集的 Aβ的聚集动力学和结合测定实验表明，h-FTAA 和 p-FTAA 要么与不同的物质相互作用，要么以不同的方式影响聚集。总之，h-FTAA 可以防止 Aβ 和 Aβ 毒性，因此表明 h-FTAA 是一种有用的工具，可以帮助我们更好地理解与细胞毒性相关的 Aβ 聚集过程。
