The most abundant component of the amyloid plaque, the hallmark of Alzheimer’s disease (AD), is the aggregation-prone amyloid-β (Aβ) peptide. Pathological aggregation of Aβ has been strongly linked to AD etiology. Insights into the local dynamics of protein aggregation is crucial for understanding the mechanisms of amyloid diseases. Herein, we fabricated Aβ mutants in which either Phe or Tyr residues were substituted with an unnatural amino acid, p-cyanophenylalanine (PheCN). We exploited PheCN’s fluorescence sensitivity to changes in hydrogen bonding to show that residues contained within the hydrophobic core region, and a residue near the core, of Aβ40 quickly participate in the initial self-association of monomers to form local structures in oligiomers. Results from a residue studied in the N-terminal region of Aβ40 suggest a more dynamic and fluctuating position in the formation of oligomers. Furthermore, we apply PheCN to study the residue-specific membrane-peptide interactions and local environmental changes of Aβ40 over the time course of aggregation. Our results suggest that (1) individual residues play unique roles in membrane-peptide interactions and (2) residue-liposome interactions change dramatically over the course of peptide aggregation.

Site-specific local environmental changes and membrane-peptide interactions of an Alzheimer’s disease peptide

2019 Spring National Meeting

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