Dataset Information

Zinc-Epigallocatechin-3-gallate Network-Coated Nanocomposites against the Pathogenesis of Amyloid-Beta.

ABSTRACT: The aggregation of amyloid beta (Aβ) is a hallmark of Alzheimer's disease (AD), a major cause of dementia and an unmet challenge in modern medicine. In this study, we constructed a biocompatible metal-phenolic network (MPN) comprising a polyphenol epigallocatechin gallate (EGCG) scaffold coordinated by physiological Zn(II). Upon adsorption onto gold nanoparticles, the MPN@AuNP nanoconstruct elicited a remarkable potency against the amyloid aggregation and toxicity of Aβ in vitro. The superior performance of MPN@AuNP over EGCG@AuNP was attributed to the porosity and hence larger surface area of the MPN in comparison with that of EGCG alone. The atomic detail of Zn(II)-EGCG coordination was unraveled by density functional theory calculations and the structure and dynamics of Aβ aggregation modulated by the MPN were further examined by discrete molecular dynamics simulations. As MPN@AuNP also displayed a robust capacity to cross a blood-brain barrier model through the paracellular pathway, and given the EGCG's function as an anti-amyloidosis and antioxidation agent, this MPN-based strategy may find application in regulating the broad AD pathology beyond protein aggregation inhibition.

SUBMITTER: Andrikopoulos N

PROVIDER: S-EPMC10037301 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Zinc-Epigallocatechin-3-gallate Network-Coated Nanocomposites against the Pathogenesis of Amyloid-Beta.

Andrikopoulos Nicholas N Li Yuhuan Y Nandakumar Aparna A Quinn John F JF Davis Thomas P TP Ding Feng F Saikia Nabanita N Ke Pu Chun PC

ACS applied materials & interfaces 20230201 6

The aggregation of amyloid beta (Aβ) is a hallmark of Alzheimer's disease (AD), a major cause of dementia and an unmet challenge in modern medicine. In this study, we constructed a biocompatible metal-phenolic network (MPN) comprising a polyphenol epigallocatechin gallate (EGCG) scaffold coordinated by physiological Zn(II). Upon adsorption onto gold nanoparticles, the MPN@AuNP nanoconstruct elicited a remarkable potency against the amyloid aggregation and toxicity of Aβ in vitro. The superior pe ...[more]

PMID: 36724494

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Project description:Numerous therapeutic agents and strategies were designed targeting the therapies of Alzheimer's disease, but many have been suspended due to their severe clinical side effects (such as encephalopathy) on patients. The attractiveness for small molecules with good biocompatibility is therefore restarted. Epigallocatechin-3-gallate (EGCG), extracted from green tea, is expected to be a promising small-molecule drug candidate, which can remodel the structure of preformed β-sheet-rich oligomers/fibrils and then effectively interfere with neurodegenerative processes. However, as the structure of non-fibrillary aggregates cannot be directly characterized, the atomic details of the underlying inhibitory and destructive mechanisms still remain elusive to date. Here, all-atom molecular dynamics simulations and experiments were carried out to elucidate the EGCG-induced remodeling mechanism of amyloid β (Aβ) fibrils. We showed that EGCG was indeed an effective Aβ fibril inhibitor. EGCG was capable of mediating conformational rearrangement of Aβ1-42 fibrils (from a β-sheet to a random coil structure) and triggering the disintegration of fibrils in a dose-dependent manner. EGCG redirected the structure of Aβ by breaking the β-sheet structure and hydrogen bonds between peptide chains within the Aβ protofibrils, especially the parallel β-strand (L17VFFAEDVGS26). Moreover, reduced solvent exposure and multisite binding patterns all tended to induce the conformation conversion of Aβ17-42 pentameric protofibrils, destroying pre-formed fibrils and inhibiting continued fibril growth. Detailed data analysis revealed that structural features of EGCG with abundant benzene ring and phenolic hydroxyl moieties preferentially interact with the parallel β-strands to effectually hinder the interaction of the interpeptide chain and the growth of the ordered β-sheet structure. Furthermore, experimental studies confirmed that EGCG was able to disaggregate the preformed fibrils and alter the protein structure. This study will enable a deeper understanding of fundamental principles for design of structural-based inhibitors.

Dataset Information

Zinc-Epigallocatechin-3-gallate Network-Coated Nanocomposites against the Pathogenesis of Amyloid-Beta.

Publications

Zinc-Epigallocatechin-3-gallate Network-Coated Nanocomposites against the Pathogenesis of Amyloid-Beta.

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