Department of Physiology, Faculty of Sciences, Charles University, Viničná 7, 12844, Prague 2, Czech Republic.
Institute of Physics, Faculty of Mathematics and Physics, Charles University, Ke Karlovu 5, 12116, Prague 2, Czech Republic.
Cell Mol Biol Lett. 2024 Nov 17;29(1):143. doi: 10.1186/s11658-024-00657-8.
Amyloid β42 (Aβ42) plays a decisive role in the pathology of Alzheimer's disease. The Aβ42 peptide can aggregate into various supramolecular structures, with oligomers being the most toxic form. However, different Aβ species that cause different effects have been described. Many cell death pathways can be activated in connection with Aβ action, including apoptosis, necroptosis, pyroptosis, oxidative stress, ferroptosis, alterations in mitophagy, autophagy, and endo/lysosomal functions. In this study, we used a model of differentiated SH-SY5Y cells and applied two different Aβ42 preparations for 2 and 4 days. Although we found no difference in the shape and size of Aβ species prepared by two different methods (NaOH or NHOH for Aβ solubilization), we observed strong differences in their effects. Treatment of cells with NaOH-Aβ42 mainly resulted in damage of mitochondrial function and increased production of reactive oxygen species, whereas application of NHOH-Aβ42 induced necroptosis and first steps of apoptosis, but also caused an increase in protective Hsp27. Moreover, the two Aβ42 preparations differed in the mechanism of interaction with the cells, with the effect of NaOH-Aβ42 being dependent on monosialotetrahexosylganglioside (GM1) content, whereas the effect of NHOH-Aβ42 was independent of GM1. This suggests that, although both preparations were similar in size, minor differences in secondary/tertiary structure are likely to strongly influence the resulting processes. Our work reveals, at least in part, one of the possible causes of the inconsistency in the data observed in different studies on Aβ-toxicity pathways.
β淀粉样蛋白 42（Aβ42）在阿尔茨海默病的病理学中起决定性作用。Aβ42 肽可以聚集形成各种超分子结构，寡聚物是最具毒性的形式。然而，已经描述了引起不同影响的不同 Aβ 物种。与 Aβ 作用相关，可以激活许多细胞死亡途径，包括细胞凋亡、坏死性凋亡、细胞焦亡、氧化应激、铁死亡、线粒体自噬、自噬和内体/溶酶体功能的改变。在这项研究中，我们使用了分化的 SH-SY5Y 细胞模型，并应用了两种不同的 Aβ42 制剂进行了 2 天和 4 天的处理。尽管我们没有发现两种不同方法（NaOH 或 NHOH 用于 Aβ 溶解）制备的 Aβ 物种在形状和大小上有差异，但我们观察到它们的作用有很大的差异。NaOH-Aβ42 处理细胞主要导致线粒体功能受损和活性氧产生增加，而 NHOH-Aβ42 的应用诱导坏死性凋亡和细胞凋亡的早期步骤，但也导致保护性 Hsp27 的增加。此外，两种 Aβ42 制剂与细胞的相互作用机制不同，NaOH-Aβ42 的作用依赖于单唾液酸四己糖神经节苷脂（GM1）含量，而 NHOH-Aβ42 的作用与 GM1 无关。这表明，尽管两种制剂的大小相似，但二级/三级结构的微小差异可能会强烈影响产生的过程。我们的工作至少部分揭示了导致不同 Aβ 毒性途径研究中观察到的数据不一致的可能原因之一。
