Effects of N-Methylated Amyloid-β_30-40 Peptides on the Fibrillation of Amyloid-β_1-40

Alzheimer's disease is a neurodegenerative disorder associated with amyloid-β (Aβ) fibrillation. N-Methylated amyloid-β peptides are potent inhibitors of amyloid-β fibrillation. We investigated the inhibitory effect of N-Methylated Aβ_30-40 peptides on Aβ_1-40 fibrillation. N-Methylated Aβ_30-40 peptides affected the fibrillation, and this effect was dependent on the concentration of N-Methylated peptide and the number and position of N-Methylated groups. N-Methylated Aβ_30-40 peptides were co-aggregated with Aβ_1-40. Spectroscopic technique was adopted to investigate an origin of the observed dependence. Suppression of thioflavin T (ThT) fluorescence count was correlated with the dissociation constant K_d of monomer-dimer equilibrium of each N-Methylated Aβ_30-40 peptide. Monomeric N-Methylated peptides decreased ThT fluorescence count during Aβ_1-40 fibrillation. Secondary structure content was not largely different between Aβ_1-40 fibrils and co-aggregates. These results suggested that N-Methylated Aβ_30-40 peptides disrupted the regular β-sheet structure of Aβ_1-40 fibrils and affected the ThT fluorescence count. The monomer-dimer equilibrium of N-Methylated peptides was (partly) responsible for the observed dependence of their inhibitory effect on the concentration of N-Methylated peptide and the number and position of N-Methylated groups. Our study provides a hint to design new N-Methylated inhibitor peptides of fibrillation.