ABSTRACT
Amyloid ß (Aß) ion channels destabilize cellular ionic homeostasis, which contributes to neurotoxicity in Alzheimer's disease. The relative roles of various Aß isoforms are poorly understood. We use bilayer electrophysiology, AFM imaging, circular dichroism, FTIR and fluorescence spectroscopy to characterize channel activities of four most prevalent Aß peptides, Aß1-42, Aß1-40, and their pyroglutamylated forms (AßpE3-42, AßpE3-40) and correlate them with the peptides' structural features. Solvent-induced fluorescence splitting of tyrosine-10 is discovered and used to assess the sequestration from the solvent and membrane insertion. Aß1-42 effectively embeds in lipid membranes, contains large fraction of ß-sheet in a ß-barrel-like structure, forms multi-subunit pores in membranes, and displays well-defined ion channel features. In contrast, the other peptides are partially solvent-exposed, contain minimal ß-sheet structure, form less-ordered assemblies, and produce irregular ionic currents. These findings illuminate the structural basis of Aß neurotoxicity through membrane permeabilization and may help develop therapies that target Aß-membrane interactions.
