Antiparallel to Parallel β-Sheet Transition of Amyloid-β is Promoted by the Ability to Incor-porate into Membranes

Alzheimer's disease is closely associated with the misfolding of amyloid-β (Aβ) peptides towards β-sheet-rich fibrils. Increasing evidence suggests that early-stage Aβ oligomers formed along the misfolding trajectory exert neurodegenerative effects by interfering with neuronal membranes eventually leading to cellular dysfunction. However, the mechanism and factors influencing these early events – particularly how the lipid membrane modulates the structural polymorphism of Aβ – remain debated. Herein, we use the enhanced plasmonic detection of surface-enhanced infrared absorption (SEIRA) spectroscopy to ask the question whether interfacial or transmembrane interactions alter the early stages of Aβ misfolding. Focusing on Aβ’s amide bands, we track the secondary structural changes when Aβ interacts with tethered bilayer lipid membranes (tBLMs) that either permit or prevent transmembrane incorporation, and quantify β-sheet fractions and orientations by comparison to computed spectra from density functional theory (DFT). We find that the incorporation of Aβ into membranes promotes the transition from antiparallel to parallel β-sheets, which are formed suddenly after a lag period indicating a cooperative process. The latter appears to be accelerated by negatively charged lipids, which are often discussed as a misfolding catalyst. Our results strengthen the proposals that misfolding involves the formation of ion channel/pore-like oligomeric structures.