Concentration of Phosphatidylserine Influence Rates of Insulin Aggregation and Toxicity of Amyloid Aggregates In Vitro.

Phosphatidylserine (PS) is a negatively charged lipid that plays a critically important role in cell apoptosis. Under physiological conditions, PS is localized on the cytosolic side of plasma membranes via ATP-dependent flippase-mediated transport. A decrease in the ATP levels in the cell, which is taken place upon pathological processes, results in the increase in PS concentration on the exterior part of the cell membranes. PS on the outer membrane surfaces attracts and activates phagocytes, which trigger cell apoptosis. This programed irreversible cell death is observed upon the progressive neurodegeneration, a hallmark of numerous amyloid associated pathologies, such as diabetes type 2 and Alzheimer's disease. In this study, we investigate the extent to which the rates of protein aggregation, which occurs upon amyloid pathologies, can be altered by the concentration of PS in large unilamellar vesicles (LUVs). We found that with an increase in the concentration of PS from 20 to 40% relative to the concentration of phosphatidylcholine and phosphatidylethanolamine, the rate of insulin aggregation, protein linked to diabetes type 2, and injection amyloidosis drastically increased. Furthermore, the concentration of PS in LUVs determined the secondary structure of protein aggregates formed in their presence. We also found that these structurally different aggregates exerted distinctly different cell toxicities. These findings suggest that a substantial decrease in cell viability, which is likely to take place upon aging, results in the increase in the concentration of PS in the outer plasma membranes, where it triggers the irreversible self-assembly of amyloidogenic proteins, which, in turn, causes the progressive neurodegeneration.