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

Abstract

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.

Elucidating the Role of Lipids in the Aggregation of Amyloidogenic Proteins

“…The results summarized in this Account also suggest that the onset and progression of amyloid diseases could be linked to the pathological changes in plasma membranes. For instance, an increase in the concentration of PS in the external membrane, which takes place in the case of cell malfunctioning, can trigger the aggregation of amyloidogenic proteins . One can expect that such changes could be linked to nutrition or molecular mechanisms responsible for the maintenance of the lipid balance in the plasma and organelle membranes.…”

“…For instance, an increase in the concentration of PS in the external membrane, which takes place in the case of cell malfunctioning, can trigger the aggregation of amyloidogenic proteins. 51 One can expect that such changes could be linked to nutrition or molecular mechanisms responsible for the maintenance of the lipid balance in the plasma and organelle membranes. Finally, the author wants to highlight that the results summarized in this Account were obtained in the in vitro experiments and therefore require additional validation in living systems to fully understand the effect of lipids on amyloidosis.…”

Insulin resistance as the molecular link between diabetes and Alzheimer's disease

“…Recent studies have highlighted a novel aspect of insulin's behavior, showing that it can aggregate into amyloid-like fibrils under specific conditions, such as changes in pH, temperature, and ionic strength, which are reminiscent of the environment found in IR[ 149 , 150 ]. This phenomenon, primarily observed in vitro, suggests a potential link between elevated insulin levels associated with IR and the formation of amyloid fibrils in the brain, akin to those seen in AD[ 151 ]. The structural similarities between insulin-derived amyloids and Aβ plaques highlight a possible mechanistic connection between metabolic dysfunctions, such as IR, and neurodegenerative processes.…”

Tubulin‐binding region alters tau–lipid interactions and changes toxicity of tau fibrils formed in the presence of phosphatidylserine lipids

“…In pre-and apoptotic cells, PS is translocated to the exterior part of the membrane (Levental et al, 2020;Matveyenka et al, 2022). If such malfunctioning cells are not eliminated by macrophages, PS domains in the plasma membrane can trigger the aggregation of misfolded proteins present close to the membrane surface (Ali et al, 2023b;Matveyenka, Zhaliazka, & Kurouski, 2023). Thus, one can expect that deceleration of the efficiency of clearance of pre-and apoptotic cells by macrophages can be the underlying cause of the abrupt protein aggregation of Tau proteins.…”