Dataset Information

RRY Inhibits Amyloid-β_1-42 Peptide Aggregation and Neurotoxicity.

ABSTRACT:

Background

Current understanding of amyloid-β protein (Aβ) aggregation and toxicity provides an extensive list of drugs for treating Alzheimer's disease (AD); however, one of the most promising strategies for its treatment has been tri-peptides.

Objective

The aim of this study is to examine those tri-peptides, such as Arg-Arg-Try (RRY), which have the potential of Aβ_1-42 aggregating inhibition and Aβ clearance.

Methods

In the present study, in silico, in vitro, and in vivo studies were integrated for screening tri-peptides binding to Aβ, then evaluating its inhibition of aggregation of Aβ, and finally its rescuing cognitive deficit.

Results

In the in silico simulations, molecular docking and molecular dynamics determined that seven top-ranking tri-peptides could bind to Aβ_1-42 and form stable complexes. Circular dichroism, ThT assay, and transmission electron microscope indicated the seven tri-peptides might inhibit the aggregation of Aβ_1-42 in vitro. In the in vivo studies, Morris water maze, ELISA, and Diolistic staining were used, and data showed that RRY was capable of rescuing the Aβ_1-42-induced cognitive deficit, reducing the Aβ_1-42 load and increasing the dendritic spines in the transgenic mouse model.

Conclusion

Such converging outcomes from three consecutive studies lead us to conclude that RRY is a preferred inhibitor of Aβ_1-42 aggregation and treatment for Aβ-induced cognitive deficit.

SUBMITTER: Sun X

PROVIDER: S-EPMC8293670 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Clinical studies have identified a correlation between type-2 diabetes mellitus and cognitive decrements en route to the onset of Alzheimer's disease (AD). Recent studies have established that post-translational modifications of the amyloid β (Aβ) peptide occur under hyperglycemic conditions; particularly, the process of glycation exacerbates its neurotoxicity and accelerates AD progression. In view of the assertion that macromolecular crowding has an altering effect on protein self-assembly, it is crucial to characterize the effects of hyperglycemic conditions via crowding on Aβ self-assembly. Toward this purpose, fully atomistic molecular dynamics simulations were performed to study the effects of glucose crowding on Aβ dimerization, which is the smallest known neurotoxic species. The dimers formed in the glucose-crowded environment were found to have weaker associations as compared to that of those formed in water. Binding free energy calculations show that the reduced binding strength of the dimers can be mainly attributed to the overall weakening of the dispersion interactions correlated with substantial loss of interpeptide contacts in the hydrophobic patches of the Aβ units. Analysis to discern the differential solvation pattern in the glucose-crowded and pure water systems revealed that glucose molecules cluster around the protein, at a distance of 5-7 Å, which traps the water molecules in close association with the protein surface. This preferential exclusion of glucose molecules and resulting hydration of the Aβ peptides has a screening effect on the hydrophobic interactions, which in turn diminishes the binding strength of the resulting dimers. Our results imply that physical effects attributed to crowded hyperglycemic environments are incapable of solely promoting Aβ self-assembly, indicating that further mechanistic studies are required to provide insights into the self-assembly of post-translationally modified Aβ peptides, known to possess aggravated toxicity, under these conditions.

Dataset Information

RRY Inhibits Amyloid-β_1-42 Peptide Aggregation and Neurotoxicity.

Background

Objective

Methods

Results

Conclusion

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Dataset Information

RRY Inhibits Amyloid-β1-42 Peptide Aggregation and Neurotoxicity.

Background

Objective

Methods

Results

Conclusion

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

RRY Inhibits Amyloid-β_1-42 Peptide Aggregation and Neurotoxicity.