Small Angle X-ray Scattering Sensing Membrane Composition: The Role of Sphingolipids in Membrane-Amyloid β-Peptide Interaction.

Abstract

Simple SummaryThe early impairments in Alzheimer’s disease are related to neuronal membrane damage. Different lipids are present in biological membranes, playing relevant physiological roles. Some of them, such as sphingomyelin, cholesterol, and ganglioside GM1, interact with each other and, importantly, with the Aβ peptide. Here, these interactions are studied using small angle X-ray scattering in model membrane systems, such as large unilamellar liposomes. This technique gives information on the width of the bilayer and reveals structural differences due to the different lipid compositions, as well as some small differences due to the presence of the Aβ peptide. The analysis highlights the concentration-dependent effect of GM1 on membrane thickness and the interaction with the Aβ-peptide, together with the inhibiting effect that the presence of sphingomyelin has on the GM1–Aβ interaction.The early impairments appearing in Alzheimer’s disease are related to neuronal membrane damage. Both aberrant Aβ species and specific membrane components play a role in promoting aggregation, deposition, and signaling dysfunction. Ganglioside GM1, present with cholesterol and sphingomyelin in lipid rafts, preferentially interacts with the Aβ peptide. GM1 at physiological conditions clusters in the membrane, the assembly also involves phospholipids, sphingomyelin, and cholesterol. The structure of large unilamellar vesicles (LUV), made of a basic POPC:POPS matrix in a proportion of 9:1, and containing different amounts of GM1 (1%, 3%, and 4% mol/mol) in the presence of 5% mol/mol sphingomyelin and 15% mol/mol cholesterol, was studied using small angle X-ray scattering (SAXS). The effect of the membrane composition on the LUVs–Aβ-peptide interaction, both for Aβ1–40 and Aβ1–42 variants, was, thus, monitored. The presence of GM1 leads to a significant shift of the main peak, towards lower scattering angles, up to 6% of the initial value with SM and 8% without, accompanied by an opposite shift of the first minimum, up to 21% and 24% of the initial value, respectively. The analysis of the SAXS spectra, using a multi-Gaussian model for the electronic density profile, indicated differences in the bilayer of the various compositions. An increase in the membrane thickness, by 16% and 12% when 2% and 3% mol/mol GM1 was present, without and with SM, respectively, was obtained. Furthermore, in these cases, in the presence of Aβ40, a very small decrease of the bilayer thickness, less than 4% and 1%, respectively, was derived, suggesting the inhibiting effect that the presence of sphingomyelin has on the GM1–Aβ interaction.