- 1:18 PM

Cell Membrane Ganglioside GM1 Mediated Amyloid-Beta Fibril Formation and Membrane Disruption

Eva Y. Chi, Shelli L. Frey, and Ka Yee C. Lee. Department of Chemistry, The University of Chicago, 5735 S. Ellis Ave., Chicago, IL 60637

Alzheimer's disease (AD) is a neurodegenerative disease affecting more than 4.5 million people in the U.S. and to date, no successful treatment is available. Although it is widely accepted that the assembly of amyloid-β peptide into insoluble fibrils is the primary event driving AD pathogenesis, the mechanism of amyloid-β fibril formation and toxicity in vivo is still unclear. In vitro studies have demonstrated that amyloid-β can aggregate at concentrations orders of magnitude lower in the presence of lipid membranes compared to bulk. In particular, the glycolipid ganglioside GM1 has been shown to accelerate fibril formation and contribute to toxicity. To gain a fundamental understanding of how GM1 mediates amyloid-β fibril formation and toxicity, we used Langmuir monolayers and vesicles to probe amyloid-β-GM1 interactions, and subsequently characterized their interactions on fibril formation and membrane morphology.

Peptide-membrane interactions were measured by constant pressure insertion assays and fibril formation was determined by incubating amyloid-β with vesicles. Lipid monolayer morphology was monitored with fluorescence microscopy and atomic force microscopy. Amyloid-β exhibited specific and favorable interaction with GM1, where peptide insertion increased with increasing GM1 content in DPPC monolayer regardless of increases in membrane rigidity at low M1 concentrations. This favorable interaction led to accelerated fibril formation when amyloid-β was incubated with POPC vesicles contained GM1 compared to those incubated without vesicles or with POPC vesicles. Insertion of amyloid-β into lipid monolayers led to the disruption of both liquid disordered and condensed domains. Our results implicate that the adsorption of amyloid-β to physiological levels of GM1 on neuronal cell surface may seed the formation of fibrils and induce disruption to the morphology of cell membrane.