Different amyloid β42 preparations induce different cell death pathways in the model of SH-SY5Y neuroblastoma cells

Abstract

Amyloid beta 42 (A beta 42) plays a decisive role in the pathology of Alzheimer's disease. The A beta 42 peptide can aggregate into various supramolecular structures, with oligomers being the most toxic form. However, different A beta species that cause different effects have been described. Many cell death pathways can be activated in connection with A beta 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 A beta 42 preparations for 2 and 4 days. Although we found no difference in the shape and size of A beta species prepared by two different methods (NaOH or NH(4)OH for A beta solubilization), we observed strong differences in their effects. Treatment of cells with NaOH-A beta 42 mainly resulted in damage of mitochondrial function and increased production of reactive oxygen species, whereas application of NH(4)OH-A beta 42 induced necroptosis and first steps of apoptosis, but also caused an increase in protective Hsp27. Moreover, the two A beta 42 preparations differed in the mechanism of interaction with the cells, with the effect of NaOH-A beta 42 being dependent on monosialotetrahexosylganglioside (GM1) content, whereas the effect of NH(4)OH-A beta 42 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 A beta-toxicity pathways.