GM1 mediates the formation and maintenance of cytotoxic Aβ oligomers

The aggregation of amyloid beta (A{beta}) peptide is associated with Alzheimers disease (AD) pathogenesis. Cell membrane composition, especially monosialotetrahexosylganglioside (GM1), is known to promote the formation of A{beta} fibrils, yet little is known about the roles of GM1 in the early steps of A{beta} oligomer formation. Here, by using GM1-contained liposomes as a mimic of neuronal cell membrane, we demonstrate that GM1 is a critical trigger of A{beta} oligomerization and aggregation. We find that GM1 not only promotes the formation of A{beta} fibrils, but also facilitates the maintenance of A{beta} oligomers on liposome membranes. We structurally characterize the A{beta} oligomers formed on the membrane and find that GM1 captures A{beta} by binding to its arginine-5 residue. To interrogate the mechanism of A{beta} oligomer toxicity, we design a new liposome-based Ca2+-encapsulation assay and provide new evidence for the A{beta} ion channel hypothesis. Finally, we conduct cell viability assay to determine the toxicity of A{beta} oligomers formed on membranes. Overall, by uncovering the roles of GM1 in mediating early A{beta} oligomer formation and maintenance, our work provides a novel direction for pharmaceutical research for AD.