Mechanism of interaction between TTR tetramer and Aβ42 oligomers: Dependence on the Aβ42 oligomeric size and morphology

Abstract

β-amyloid (Aβ) deposits are the leading cause of Alzheimer's disease. Many studies have confirmed that transthyretin (TTR) inhibits the cytotoxicity of Aβ oligomers (AβOs) with various species (oligomers and protofibrils, but not monomers) through their interactions. Here, we investigated the mechanisms of interactions between the TTR tetramer and various Aβ species, including two monomers with different morphologies and four oligomers with different molecular weights, by employing molecular dynamics simulations. From these results, we propose a clear interaction scenario: upon AβO binding, the dimer−dimer distance of TTR increases and the binding energy decreases, indicating an unfavorable effect on the TTR stability. Moreover, the larger the molecular weight (MW) of AβO, the greater the effect of interaction between the TTR tetramer and Aβ oligomer, and consequently the worse the TTR stability. In turn, Aβ-Aβ intermolecular distances in AβO grow and the hydrophobic solvent-accessible surface area (SASA) increases, whereas the number of intermolecular hydrogen bonds decreases, indicating AβO disaggregation induced by the TTR binding. Moreover, a trend is observed for the disaggregation to increase as the MW of the AβO species increases. Finally, we reveal that conformations rich in helical sections rather than the semi-extended conformation are favored upon binding with TTR. Overall, this study provides a comprehensive molecular-level insight to better understand the mechanism and principles of interaction between the TTR tetramer and AβOs.

Keywords

Transthyretin / Aβ oligomer / Mechanism of interaction / Molecular weight / Dependence

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

CRediT authorship contribution statement

Jinfei Mei: Writing - original draft, Validation, Investigation, Formal analysis, Data curation, Conceptualization. Wenqi Gao: Writing - original draft, Visualization, Software, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Yvning Guan: Software, Methodology, Investigation. Sajjad Ahmad: Validation, Investigation. Fahad Nouman Muhammad: Visualization, Validation. Hongqi Ai: Writing - review & editing, Supervision, Resources, Project administration, Funding acquisition, Conceptualization.

Acknowledgements

This work was supported by the Shandong Provincial Natural Science Foundation (ZR2022MB073) of China.

Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.chphma.2024.12.006. The docking structure of TTR-A 𝛽 42 systems; Overall and local magnification of key residues on the interfaces between TTR tetramer and A 𝛽 O; Helix content (%) of A 𝛽 monomer before and after MD.

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