Structural convergence and membrane interactions of Aβ_1-42 along the primary nucleation process studied by solid...

Non-specific disruption of cellular membranes induced by amyloidogenic aggregation of β-amyloid (Aβ) peptides remains a viable cytotoxicity mechanism in Alzheimer's disease (AD). Obtaining structural information about the intermediate states of Aβ-membrane systems and their molecular interactions is challenging due to their heterogeneity and low abundance. Here, we systematically study the molecular interactions of membrane-associated Aβ_1-42 peptides using solid-state nuclear magnetic resonance (ssNMR) spectroscopy, focusing on the primary nucleation phase of the fibrillation process. Compared to the less pathogenic Aβ_1-40 peptide, Aβ_1-42 forms smaller oligomers prior to fibrillation, as evidenced by a higher overall population of lipid-proximity peptides. Aβ_1-42 also exhibits more pronounced residue-specific contacts with phospholipid headgroups compared to Aβ_1-40, with multiple lipid-proximity segments throughout the entire primary sequence. The segments involved in initial inter-strand assembly overlap with those located near the lipid headgroups in Aβ_1-42, whereas these two segments are distinct in Aβ_1-40. ssNMR spectroscopy with sensitivity enhanced by Dynamic nuclear polarization (DNP) confirmed local secondary structural convergence during the nucleation process of Aβ_1-42 and the presence of long-range tertiary contacts at early stages of nucleation. Overall, our results provide a molecular-level understanding of the Aβ_1-42 nucleation process in a membrane-like environment and its membrane-disrupting intermediates. The comparison between Aβ_1-42 and Aβ_1-40 explains its higher cytotoxicity from the perspective of membrane disruption.