The structure of tyrosine-10 favors ionic conductance of Alzheimer's disease-associated full-length amyloid- channels

Amyloid beta (A beta) ion channels destabilize cellular ionic homeostasis, which contributes to neurotoxicity in Alzheimer's disease. The relative roles of various A beta isoforms are poorly understood. We use bilayer electrophysiology, AFM imaging, circular dichroism, FTIR and fluorescence spectroscopy to characterize channel activities of four most prevalent A beta peptides, A beta 1-42, A beta 1-40, and their pyroglutamylated forms (A beta pE3-42, A beta pE3-40) 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. A beta 1-42 effectively embeds in lipid membranes, contains large fraction of beta-sheet in a beta-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 beta-sheet structure, form less-ordered assemblies, and produce irregular ionic currents. These findings illuminate the structural basis of A beta neurotoxicity through membrane permeabilization and may help develop therapies that target A beta-membrane interactions. The structural basis of membrane permeabilization by Alzheimer's disease-related amyloid beta (A beta) peptides is elucidated. Membrane insertion of tyrosine-10 supports the most effective ionic conductance of the full-length A beta 1-42 compared to other isoforms.