Lipid Oxidation Effect on Membrane Properties in Phosphatidylinositol- and Phosphatidylserine-Enriched Neuronal Biomimetic Models

Oxidative stress is a key driver of neurodegenerative diseases, yet its impact on the mechanical properties of complex neuronal membranes remains poorly defined. A combined computational and experimental bottom-up approach was employed to study biomimetic membranes, ranging from simple bilayers to complex mixtures mimicking human neuronal composition. The results indicated that oxidation influenced all investigated membrane properties. While a decrease in membrane thickness and area compressibility was observed across all systems, trends for bending rigidity, area per lipid, and diffusion coefficients remained inconsistent in the simpler models. A significant influence of phosphatidylinositol and cholesterol on these properties was identified. Experimental giant unilamellar vesicles (GUVs) exhibited oxidation levels between 2% and 17%, with cholesterol-rich mixtures demonstrating higher susceptibility to peroxidation. Furthermore, an approach is proposed that demonstrates that deviations in experimentally obtained bending rigidity can be partially explained by the level of oxidation. This study emphasizes that accounting for oxidation is crucial for accurately modeling the mechanical behavior of neurological membranes.