RT Journal Article
SR Electronic
T1 GM1 mediates the formation and maintenance of cytotoxic Aβ oligomers
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.07.22.453392
DO 10.1101/2021.07.22.453392
A1 Dong Yan Zhang
A1 Jian Wang
A1 Rebecca M. Fleeman
A1 Madison K. Kuhn
A1 Matthew T. Swulius
A1 Elizabeth A. Proctor
A1 Nikolay V. Dokholyan
YR 2021
UL http://biorxiv.org/content/early/2021/07/22/2021.07.22.453392.abstract
AB The aggregation of 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 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 Aβ oligomers on liposome membranes. We structurally characterize the Aβ oligomers formed on the membrane and find that GM1 captures Aβ by binding to its arginine-5 residue. To interrogate the mechanism of Aβ oligomer toxicity, we design a new liposome-based Ca2+-encapsulation assay and provide new evidence for the Aβ ion channel hypothesis. Finally, we conduct cell viability assay to determine the toxicity of Aβ 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.Competing Interest StatementThe authors have declared no competing interest.