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

Phosphatidylserine (PS) is a negativelycharged lipid that playsa critically important role in cell apoptosis. Under physiologicalconditions, PS is localized on the cytosolic side of plasma membranesvia ATP-dependent flippase-mediated transport. A decrease in the ATPlevels in the cell, which is taken place upon pathological processes,results in the increase in PS concentration on the exterior part ofthe cell membranes. PS on the outer membrane surfaces attracts andactivates phagocytes, which trigger cell apoptosis. This programedirreversible cell death is observed upon the progressive neurodegeneration,a hallmark of numerous amyloid associated pathologies, such as diabetestype 2 and Alzheimer's disease. In this study, we investigatethe extent to which the rates of protein aggregation, which occursupon amyloid pathologies, can be altered by the concentration of PSin large unilamellar vesicles (LUVs). We found that with an increasein the concentration of PS from 20 to 40% relative to the concentrationof phosphatidylcholine and phosphatidylethanolamine, the rate of insulinaggregation, protein linked to diabetes type 2, and injection amyloidosisdrastically increased. Furthermore, the concentration of PS in LUVsdetermined the secondary structure of protein aggregates formed intheir presence. We also found that these structurally different aggregatesexerted distinctly different cell toxicities. These findings suggestthat a substantial decrease in cell viability, which is likely totake place upon aging, results in the increase in the concentrationof PS in the outer plasma membranes, where it triggers the irreversibleself-assembly of amyloidogenic proteins, which, in turn, causes theprogressive neurodegeneration.