Monosialotetrahexosylganglioside Promotes Early Aβ42 Oligomer Formation and Maintenance

The aggregation of the amyloid beta
(Aβ) peptide is associated
with Alzheimer’s disease (AD) pathogenesis. Cell membrane composition,
especially monosialotetrahexosylganglioside (GM1), is known to promote
the formation of Aβ fibrils, yet little is known about the roles
of GM1 in the early steps of Aβ 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 Aβ oligomerization
and aggregation. We find that GM1 not only promotes the formation
of Aβ fibrils but also facilitates the maintenance of Aβ42
oligomers on liposome membranes. We structurally characterize the
Aβ42 oligomers formed on the membrane and find that GM1 captures
Aβ by binding to its arginine-5 residue. To interrogate the
mechanism of Aβ42 oligomer toxicity, we design a new liposome-based
Ca2+-encapsulation assay and provide new evidence for the
Aβ42 ion channel hypothesis. Finally, we determine the toxicity
of Aβ42 oligomers formed on membranes. Overall, by uncovering
the roles of GM1 in mediating early Aβ oligomer formation and
maintenance, our work provides a novel direction for pharmaceutical
research for AD.