Effects of Aβ-derived peptide fragments on fibrillogenesis of Aβ

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.

Aβ8-20 Fragment as an Anti-Fibrillogenic and Neuroprotective Agent: Advancing toward Efficient Alzheimer’s Disease Treatment

“…Circular dichroism (CD) experiments, performed in a time range of 96 h (Figure b), reveal that Aβ 8‑20 adopts a random coil conformation over time. Interestingly, our results differ from those obtained by Abedin et al for the Aβ 11‑20 fragment which shows, despite the high sequence homology, a high propensity to form a β-sheet-rich structure . The absence of any significant secondary structure transition, typical of amyloid fiber formation, supports well ThT results, although it is not possible to exclude the formation of amorphous aggregates.…”

“…Interestingly, CD spectra (Figure b, inset) reveal a mixture of the random coil and β-sheet structure at t = 0 which evolves over 24 h into a random coil/α-helix. Thus, our data suggest that Aβ 8‑20 could interfere with the aggregation process of both Aβ 1‑40 and Aβ 1‑42 already at a 1:1 molar ratio, suggesting a higher efficiency than, for example, that of Aβ 11‑20 …”

“…Several fragments of Aβ have been shown to undergo amyloidogenic aggregation. , Although Aβ 8‑20 lacks the aggregation-prone C-terminus region and residues in the N-terminus responsible for amyloid fiber stabilization, we could not rule out the possibility that this fragment may form amyloid aggregates. To evaluate the aggregation properties of Aβ 8‑20 , we initially performed a well-known thioflavin T (ThT) assay.…”

“…Aβ undergoes several post-translational modifications, including the formation of truncated species as the result of physiological enzymatic cleavage. − Many truncated forms of Aβ have been identified in blood plasma samples and human cerebrospinal fluids of AD patients . Recently, Abedin et al reported a structural and aggregation propensity study of seven Aβ fragments with the aim of identifying the region of Aβ which is able to inhibit fibrillogenesis . Generally, truncated forms of Aβ are of particular interest since they are known to affect the Aβ aggregation rate.…”

Small Molecules N-Phenylbenzofuran-2-carboxamide and N-Phenylbenzo[b]thiophene-2-carboxamide Promote Beta-Amyloid (Aβ42) Aggregation and Mitigate Neurotoxicity

“…Previous studies on Aβ42 aggregation have shown that the 16 KLVFFAE 22 and C-terminal 29 GAIIGLMVGGVVIA 42 regions exhibit faster aggregation propensities. 60 Both compounds 7a and 7b contain planar aromatic bicyclic ring systems (either a benzofuran or a benzothiophene ring) along with a phenyl ring. Molecular docking studies show that the aromatic bicyclic and phenyl rings present in these two compounds can undergo π-alkyl interactions with nonpolar amino acids including Leu17, Val18, Al21, and Leu34.…”