Instituto de Bioquímica Médica Leopoldo de Meis, Programa de Biologia Estrutural, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro 21941-590, Brazil.
Fiocruz Pernambuco, Departamento de Microbiologia, Instituto Aggeu Magalhães, Recife, Pernambuco 50740-465, Brazil.
ACS Biomater Sci Eng. 2020 Aug 10;6(8):4414-4423. doi: 10.1021/acsbiomaterials.0c00188. Epub 2020 Jul 9.
The accumulation of cross-β-sheet amyloid fibrils is a hallmark of all human amyloid diseases. The compound epigallocatechin-3-gallate (EGCG), the main polyphenol present in green tea, has been described to have beneficial effects in several pathologies, including amyloidogenic diseases. This polyphenol blocks amyloidogenesis and disaggregates a broad range of amyloidogenic peptides comprising amyloid fibrils . The mechanism by which EGCG acts in the context of amyloid aggregation is not clear. Most of the biological effects of EGCG are attributable to its antioxidant activity. However, EGCG-oxidized products appear to be sufficient for the majority of EGCG amyloid remodeling observed against some polypeptides. If controlled, EGCG oxidation can afford homogenous microparticles (MPs) and can serve as drug delivery agents. Herein, we produced EGCG MPs by oxidative coupling and analyzed their activity during the aggregation of the protein α-synuclein (α-syn), the main protein related to Parkinson's disease. The MPs modestly remodeled mature amyloid fibrils and efficiently inhibited the amyloidogenic aggregation of α-syn. The MPs showed low cytotoxicity against both dopaminergic cells and microglial cells. The MPs reduced the cytotoxic effects of α-syn oligomers. Interestingly, the MPs were loaded with another antiamyloidogenic compound, increasing their activity against amyloid aggregation. We propose the use of EGCG MPs as a bifunctional strategy, blocking amyloid aggregation directly and carrying a molecule that can act synergistically to alleviate the symptoms caused by the amyloidogenic pathway.
β-折叠片层交叉的淀粉样纤维的积累是所有人类淀粉样变疾病的标志。儿茶素没食子酸酯（EGCG）是绿茶中主要的多酚，已被描述为在多种疾病中具有有益作用，包括淀粉样变性疾病。这种多酚可以阻止淀粉样蛋白的形成并使广泛的淀粉样蛋白肽解聚，包括淀粉样纤维。EGCG 在淀粉样蛋白聚集背景下的作用机制尚不清楚。EGCG 的大多数生物学效应归因于其抗氧化活性。然而，EGCG 氧化产物似乎足以使大多数针对某些多肽观察到的 EGCG 淀粉样蛋白重塑。如果控制得当，EGCG 氧化可以提供均一的微粒（MPs），并可以作为药物递送剂。本文通过氧化偶联生产 EGCG MPs，并分析了它们在与帕金森病相关的主要蛋白α-突触核蛋白（α-syn）聚集过程中的活性。MPs 适度重塑成熟的淀粉样纤维，并有效地抑制 α-syn 的淀粉样聚集。MPs 对多巴胺能细胞和小胶质细胞均表现出低细胞毒性。MPs 降低了α-syn 低聚物的细胞毒性作用。有趣的是，MPs 负载了另一种抗淀粉样蛋白形成的化合物，从而提高了它们对淀粉样蛋白聚集的活性。我们建议使用 EGCG MPs 作为一种双功能策略，直接阻止淀粉样蛋白聚集并携带一种可以协同作用以减轻淀粉样蛋白途径引起的症状的分子。
