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

作者：Dong Yan Zhang, Jian Wang, Gangtong Huang, Martin Dokholyan, Smaranda Willcox, Jack D. Griffith, Feng Ding, Nikolay V. Dokholyan · 发表于：Journal of Biological Chemistry · 年份：2025 · DOI：10.1016/j.jbc.2025.110778 · 被引用次数：5 · 研究领域：Glycosylation and Glycoproteins Research、Lipid metabolism and disorders、Pancreatitis Pathology and Treatment

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 modi...