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Dependence of the Formation of Tau and Aβ Peptide Mixed Aggregates on the Secondary Structure of the N-Terminal Region of Aβ.

ABSTRACT: One of the hallmarks of Alzheimer's disease is the formation of aggregates of the tau protein, a process that can be facilitated by the presence of fibrils formed by the amyloid β peptide (Aβ). However, the mechanism that triggers tau aggregation is still a matter of debate. The effect of Aβ₄₀ fibrils on the aggregation of the repeat domain of tau (TauRD) is investigated here by employing coarse-grained molecular dynamics simulations. The results indicate that the repeat domain of tau has a high affinity for Aβ₄₀ fibrils, with the ₂₆₁GSTENLK₂₆₇ fragment of tau driving TauRD toward the ₁₆KLVFFA₂₁ fragment in Aβ₄₀. Monomeric Aβ₄₀, in which the ₁₆KLVFFA₂₁ fragment is rarely found in an extended conformation (as in the fibril), has a low affinity for the TauRD, indicating that the ability of Aβ₄₀ fibrils to bind to the TauRD depends on the ₁₆KLVFFA₂₁ fragment of Aβ adopting an extended conformation.

SUBMITTER: Rojas AV

PROVIDER: S-EPMC6524542 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Dependence of the Formation of Tau and Aβ Peptide Mixed Aggregates on the Secondary Structure of the N-Terminal Region of Aβ.

Rojas Ana V AV Maisuradze Gia G GG Scheraga Harold A HA

The journal of physical chemistry. B 20180710 28

One of the hallmarks of Alzheimer's disease is the formation of aggregates of the tau protein, a process that can be facilitated by the presence of fibrils formed by the amyloid β peptide (Aβ). However, the mechanism that triggers tau aggregation is still a matter of debate. The effect of Aβ<sub>40</sub> fibrils on the aggregation of the repeat domain of tau (TauRD) is investigated here by employing coarse-grained molecular dynamics simulations. The results indicate that the repeat domain of tau ...[more]

PMID: 29940109

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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.

Dataset Information

Dependence of the Formation of Tau and Aβ Peptide Mixed Aggregates on the Secondary Structure of the N-Terminal Region of Aβ.

Publications

Dependence of the Formation of Tau and Aβ Peptide Mixed Aggregates on the Secondary Structure of the N-Terminal Region of Aβ.

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