RÉSUMÉ
In Alzheimer's disease, the amyloid-beta peptide (Aß) is implicated in neuronal toxicity via interactions with the cell membrane. Monomeric Aß (Aßm) is intrinsically disordered, but it can adopt a range of aggregated conformations with varying toxicities from short fibrillar oligomers (FO), to globular nonfibrillar oligomers (NFO), and full-length amyloid fibrils. NFO is considered to be the most toxic, followed by fibrils, and finally Aßm. To elucidate molecular-level membrane interactions that contribute to their different toxicities, we used liquid surface X-ray scattering and Langmuir trough insertion assays to compare Aßm, FO, and NFO surface activities and interactions with anionic DMPG lipid monolayers at the air/water interface. All Aß species were highly surface active and rapidly adopted ß-sheet rich structures upon adsorption to the air/water interface. Likewise, all Aß species had affinity for the anionic membrane. Aßm rapidly converted to ß-sheet rich assemblies upon binding the membrane, and these aggregated structures of Aßm and FO disrupted hexagonally packed lipid domains and resulted in membrane thinning and instability. In contrast, NFO perturbed membrane structure by extracting lipids from the air/water interface and causing macroscale membrane deformations. Altogether, our results support two models for membrane-mediated Aß toxicity: fibril-induced reorganization of lipid packing and NFO-induced membrane destabilization and lipid extraction. This work provides a structural understanding of Aß neurotoxicity via membrane interactions and aids the effort in understanding early events in Alzheimer's disease and other neurodegenerative diseases.