Effects of A\u03b2-derived peptide fragments on fibrillogenesis of A\u03b2

Faisal Abedin,Nabin Kandel,Suren A. Tatulian

doi:10.1038/s41598-021-98644-y

Abstract

Amyloid 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.

Highlights

Amyloid β (Aβ) peptide aggregation plays a central role in Alzheimer’s disease (AD) etiology
The results facilitate a better understanding of segment-specific properties of Aβ1–42 and identify peptide fragments capable of inhibiting its aggregation
Use of overlapping sequences was important for characterization of segments at boundaries of consecutive stretches; properties of the boundary between P(i) and P(i + 2) were reflected in P(i + 1), which covers the C- and N-termini of flanking sequences

Summary

Introduction

Amyloid β (Aβ) peptide aggregation plays a central role in Alzheimer’s disease (AD) etiology. 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. The total Aβ pool in human brain is a heterogenous assembly of peptide species of different size and with distinct structural features and toxicities[12,13,14,15,16,17]. Aβ1–40 monomers in the fibrillar structure adopt a U-shaped conformation with two β-strands (residues 10–22 and 30–40) separated by a loop and with unordered N-terminus[31] (Fig. 1). Toxicity depends on particular Aβ species, the aggregation state, and the structural features of peptide assemblies[3,20,35,36,37,38]. Aβ1–40 is found in higher concentrations than Aβ1–42, but the latter is more toxic, which is believed to result from its increased hydrophobicity

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