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 G_M1 has been shown to accelerate fibril formation and contribute to toxicity. To gain a fundamental understanding of how G_M1 mediates amyloid-β fibril formation and toxicity, we used Langmuir monolayers and vesicles to probe amyloid-β-G_M1 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 G_M1, where peptide insertion increased with increasing G_M1 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 G_M1 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 G_M1 on neuronal cell surface may seed the formation of fibrils and induce disruption to the morphology of cell membrane.