Misfolded protein oligomers induce an increase of intracellular Ca2+ causing an escalation of reactive oxidative species.

Giulia Fani, Chiara Ester La Torre, Roberta Cascella, Cristina Cecchi, Michele Vendruscolo, Fabrizio Chiti

Cellular and molecular life sciences : CMLS 2022 Aug 27

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Alzheimer's disease is characterized by the accumulation in the brain of the amyloid β (Aβ) peptide in the form of senile plaques. According to the amyloid hypothesis, the aggregation process of Aβ also generates smaller soluble misfolded oligomers that contribute to disease progression. One of the mechanisms of Aβ oligomer cytotoxicity is the aberrant interaction of these species with the phospholipid bilayer of cell membranes, with a consequent increase in cytosolic Ca2+ levels, flowing from the extracellular space, and production of reactive oxygen species (ROS). Here we investigated the relationship between the increase in Ca2+ and ROS levels immediately after the exposure to misfolded protein oligomers, asking whether they are simultaneous or instead one precedes the other. Using Aβ42-derived diffusible ligands (ADDLs) and type A HypF-N model oligomers (OAs), we followed the kinetics of ROS production and Ca2+ influx in human neuroblastoma SH-SY5Y cells and rat primary cortical neurons in a variety of conditions. In all cases we found a faster increase of intracellular Ca2+ than ROS levels, and a lag phase in the latter process. A Ca2+-deprived cell medium prevented the increase of intracellular Ca2+ ions and abolished ROS production. By contrast, treatment with antioxidant agents prevented ROS formation, did not prevent the initial Ca2+ flux, but allowed the cells to react to the initial calcium dyshomeostasis, restoring later the normal levels of the ions. These results reveal a mechanism in which the entry of Ca2+ causes the production of ROS in cells challenged by aberrant protein oligomers. © 2022. The Author(s).

Citation

Giulia Fani, Chiara Ester La Torre, Roberta Cascella, Cristina Cecchi, Michele Vendruscolo, Fabrizio Chiti. Misfolded protein oligomers induce an increase of intracellular Ca2+ causing an escalation of reactive oxidative species. Cellular and molecular life sciences : CMLS. 2022 Aug 27;79(9):500