Journal
ACS CHEMICAL NEUROSCIENCE
Volume -, Issue -, Pages -Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.2c00221
Keywords
amyloid beta; GM1; amyloid beta-membrane interaction; A beta aggregation; A beta oligomer toxicity; ion channel
Funding
- National Institutes of Health [1R35 GM134864]
- Huck Institutes of the Life Sciences
- Passan Foundation
- National Center for Advancing Translational Sciences, National Institutes of Health [UL1 TR002014]
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The role of monosialotetrahexosylganglioside (GM1) in the early formation and maintenance of amyloid beta (A beta) oligomers in Alzheimer's disease (AD) has been uncovered. GM1 not only promotes the formation of A beta fibrils but also facilitates the maintenance of A beta oligomers on cell membranes. The study provides new evidence for the toxicity mechanisms of A beta oligomers and suggests a novel direction for pharmaceutical research on AD.
The aggregation of the amyloid beta (A beta) peptide is associated with Alzheimer's 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 the 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 42 oligomers on liposome membranes. We structurally characterize the A beta 42 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 42 oligomer toxicity, we design a new liposome-based Ca2+-encapsulation assay and provide new evidence for the A beta 42 ion channel hypothesis. Finally, we determine the toxicity of A beta 42 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.
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