Monosialotetrahexosylganglioside Promotes Early Aß42 Oligomer Formation and Maintenance.

ABSTRACT

The aggregation of the amyloid beta (Aß) peptide is associated with Alzheimer's disease (AD) pathogenesis. Cell membrane composition, especially monosialotetrahexosylganglioside (GM1), is known to promote the formation of Aß fibrils, yet little is known about the roles of GM1 in the early steps of Aß oligomer formation. Here, by using GM1-contained liposomes as a mimic of the neuronal cell membrane, we demonstrate that GM1 is a critical trigger of Aß oligomerization and aggregation. We find that GM1 not only promotes the formation of Aß fibrils but also facilitates the maintenance of Aß42 oligomers on liposome membranes. We structurally characterize the Aß42 oligomers formed on the membrane and find that GM1 captures Aß by binding to its arginine-5 residue. To interrogate the mechanism of Aß42 oligomer toxicity, we design a new liposome-based Ca2+-encapsulation assay and provide new evidence for the Aß42 ion channel hypothesis. Finally, we determine the toxicity of Aß42 oligomers formed on membranes. Overall, by uncovering the roles of GM1 in mediating early Aß oligomer formation and maintenance, our work provides a novel direction for pharmaceutical research for AD.