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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 Aβ_1-42 peptide and seven overlapping peptide fragments have been studied, i.e. Aβ_1-10 (P1), Aβ_6-15 (P2), Aβ_11-20 (P3), Aβ_16-25 (P4), Aβ_21-30 (P5), Aβ_26-36 (P6), and Aβ_31-42 (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 Aβ_1-42, whereas P7 and P2 displayed moderate inhibitory potency. It is proposed that P3 and P6 intercalate between Aβ_1-42 molecules and thereby inhibit Aβ_1-42 aggregation. These findings may facilitate therapeutic strategies of inhibition of Aβ fibrillogenesis by Aβ-derived peptides.

SUBMITTER: Abedin F

PROVIDER: S-EPMC8479085 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionThe misfolding and aggregation of β-amyloid (Aβ) easily form Aβ fibers, which are continuously deposited in the brain, leading to the massive generation of amyloid plaques, severely destroying neuronal connections, and promoting Alzheimer's disease (AD) The occurrence and development of AD is one of the pathogenesis of AD. There is an urgent need to develop inhibitors against Aβ aggregation, which is hopefully a potential way to treat AD.MethodsIn this study, we first found the crystal structure of the Aβ1-42 receptor protein from the RCSB PDB protein structure database and used the SYBYL X2.0 software for molecular docking, and then used the Peptide Ranker, Innovagen, DPL, and ToxinPred online websites to perform peptides. Predict the activity score, toxicity and water solubility, and then calculate the affinity constant KD value of polypeptide and Aβ through Surface Plasmon Resonance (SPR) experiment. Subsequently, the CCK-8 kit method was used to determine the toxicity of different concentrations of peptides (3.125, 6.25, 12.5, 25, 50, 100, 200 μM) to PC12 cells, and then the peptides and Aβ according to different concentration ratios (1:4, 1:2, 1:1, 1:0.5, 1:0.25, 0:4), this method is also used to detect the effect of peptides on Aβ-induced neurotoxicity. The thioflavin T (ThT) fluorescence method was used to detect the effects of peptides (50 μM) on Aβ (25 μM) aggregation inhibitory effect.ResultsThe results showed that the CScore of YVRHLKYVRHLK peptide molecule docking was 10.0608, the predicted activity score was 0.20, and the KD value was 5.385 × 10-5. The ThT and CCK-8 kit method found that the peptide itself is less toxic to PC12 cells at a concentration of 50 μM, and it has a significant inhibitory effect on the formation of Aβ1-42 aggregates when incubated with Aβ1-42 at a ratio of 1:1 (p < 0.05) and can significantly reduce the PC12 cytotoxicity induced by Aβ1-42 (p < 0.05).ConclusionIn conclusion, the polypeptide YVRHLKYVRHLK designed in this study has a neuroprotective effect on PC12 cytotoxicity induced by Aβ1-42. Graphical Abstract.

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Effects of Aβ-derived peptide fragments on fibrillogenesis of Aβ.

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