APOE regulates the transport of GM1

We hypothesize that GM1, a ganglioside abundant in cell membranes, particularly in the nervous system, may serve as the missing link between APOE and Aβ pathology. We find that both APOE3 and APOE4 exhibit superior binding affinity to GM1 compared to cholesterol and have an enhanced cellular uptake to GM1 lipid structures than cholesterol lipid structures. APOE regulates the transport process of GM1 depending on the cell type, which is influenced by the expression of APOE receptors in different cell lines and alters GM1 contents in cell membranes. We also find that the presence of GM1 alters the secondary structure of APOE3 and APOE4 and enhances the binding affinity between APOE and its receptor low-density lipoprotein receptor (LDLR), consequently promoting the cellular uptake of lipid structures in the presence of APOE. To understand the enhanced cellular uptake observed in lipid structures containing 20% GM1, we determined the distribution of GM1 on the membrane and found that GM1 clustering in lipid rafts, thereby supporting the physiological interaction between APOE and GM1. Overall, we find that APOE plays a regulatory role in GM1 transport, and the presence of GM1 on the lipid structures influences this transport process.