Apolipoprotein E (APOE) regulates the transport of monosialotetrahexosylganglioside (GM1).

Apolipoprotein E (APOE) is a key lipid transporter involved in the trafficking and clearance. The ε4 allele of APOE (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), and certain lipids are closely linked to AD pathology. APOE may contribute to AD pathogenesis through its lipid transport function. Although cholesterol is a well-established cargo of APOE and has been associated with AD, its role as a mechanistic link between APOE and AD has not been demonstrated. Here, we demonstrate that monosialotetrahexosylganglioside (GM1), a membrane lipid implicated in AD, is a preferential binder of APOE. We have previously shown that GM1 promotes amyloid beta (Aβ) oligomer aggregation, which is a critical step in AD pathology. Here, we show that APOE binds GM1 with higher affinity than cholesterol and facilitates greater cellular uptake of GM1-containing lipid structures in a cell-type-dependent manner. Furthermore, GM1 alters the secondary structure of APOE and enhances its interaction with the low-density lipoprotein receptor, thereby promoting the internalization of lipid assemblies. Using confocal imaging and discrete molecular dynamics simulations, we show that membranes containing 20% GM1 form stable stripe-like clusters, consistent with the formation of GM1-enriched lipid rafts that may serve as physiological platforms for APOE:GM1 interactions. These results reveal a reciprocal relationship in which APOE regulates GM1 transport, while GM1 modifies APOE function and localization. The competition between GM1 and cholesterol for APOE binding may contribute to cholesterol dysregulation in APOE4 carriers. Our results uncover a novel mechanistic link between APOE and AD pathogenesis through GM1-mediated promotion of Aβ aggregation.