AbstractAmyloid β (Aβ) peptide aggregation plays a central role in Alzheimer’s disease (AD) etiology. AD drug candidates have included small molecules or peptides directed towards inhibition of Aβ fibrillogenesis. Although some Aβ-derived peptide fragments suppress Aβ fibril growth, comprehensive analysis of inhibitory potencies of peptide fragments along the whole Aβ sequence has not been reported. The aim of this work is (a) to identify the region(s) of Aβ with highest propensities for aggregation and (b) to use those fragments to inhibit Aβ fibrillogenesis. Structural and aggregation properties of the parent Aβ1–42 peptide and seven overlapping peptide fragments have been studied, i.e. Aβ1–10 (P1), Aβ6–15 (P2), Aβ11–20 (P3), Aβ16–25 (P4), Aβ21–30 (P5), Aβ26–36 (P6), and Aβ31–42 (P7). Structural transitions of the peptides in aqueous buffer have been monitored by circular dichroism and Fourier transform infrared spectroscopy. Aggregation and fibrillogenesis were analyzed by light scattering and thioflavin-T fluorescence. The mode of peptide-peptide interactions was characterized by fluorescence resonance energy transfer. Three peptide fragments, P3, P6, and P7, exhibited exceptionally high propensity for β-sheet formation and aggregation. Remarkably, only P3 and P6 exerted strong inhibitory effect on the aggregation of Aβ1–42, whereas P7 and P2 displayed moderate inhibitory potency. It is proposed that P3 and P6 intercalate between Aβ1–42 molecules and thereby inhibit Aβ1–42 aggregation. These findings may facilitate therapeutic strategies of inhibition of Aβ fibrillogenesis by Aβ-derived peptides.
Inhibitory effect of hydrophobic fullerenes on the β-sheet-rich oligomers of a hydrophilic GNNQQNY peptide revealed by atomistic simulations
