Green Tea Polyphenol Epigallocatechin-Gallate in Amyloid Aggregation and Neurodegenerative Diseases

Abstract

The accumulation of protein aggregates in human tissues is a hallmark of more than 40 diseases called amyloidoses. In seven of these disorders, the aggregation is associated with neurodegenerative processes in the central nervous system such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). The aggregation occurs when certain soluble proteins lose their physiological function and become toxic amyloid species. The amyloid assembly consists of protein filament interactions, which can form fibrillar structures rich in β-sheets. Despite the frequent incidence of these diseases among the elderly, the available treatments are limited and at best palliative, and new therapeutic approaches are needed. Among the many natural compounds that have been evaluated for their ability to prevent or delay the amyloidogenic process is epigallocatechin-3-gallate (EGCG), an abundant and potent polyphenolic molecule present in green tea that has extensive biological activity. There is evidence for EGCG’s ability to inhibit the aggregation of α-synuclein, amyloid-β, and huntingtin proteins, respectively associated with PD, AD, and HD. It prevents fibrillogenesis (in vitro and in vivo), reduces amyloid cytotoxicity, and remodels fibrils to form non-toxic amorphous species that lack seed propagation. Although it is an antioxidant, EGCG in an oxidized state can promote fibrils’ remodeling through formation of Schiff bases and crosslinking the fibrils. Moreover, microparticles to drug delivery were synthesized from oxidized EGCG and loaded with a second anti-amyloidogenic molecule, obtaining a synergistic therapeutic effect. Here, we describe several pre-clinical and clinical studies involving EGCG and neurodegenerative diseases and their related mechanisms.

Functional Bacterial Amyloids: Understanding Fibrillation, Regulating Biofilm Fibril Formation and Organizing Surface Assemblies

“…A prime example is the polyphenol epigallocatechin-3-gallate (EGCG) (Figure 8a), which inhibits the formation of both pathological amyloid [103][104][105][106] and FuBA [40]. Although EGCG has shown promising pre-clinical results against pathological amyloids, the compound has not successfully passed clinical trials, possibly because of low chemical stability in vivo (it is prone to epimerization and auto-oxidation above pH 6 [107]) and limited penetration of the blood-brain barrier [106,108]. While EGCG also can inhibit the formation of bacterial amyloid and reduce biofilm formation [40,109], stability issues have also hampered its clinical use against infections [110][111][112].…”

Myricetin Inhibits α‐Synuclein Amyloid Aggregation by Delaying the Liquid‐to‐Solid Phase Transition

“…It is well‐known that a number of phenolic compounds have the ability to inhibit the abnormal aggregation of amyloid proteins [20–25] . For example, apigenin could reduce human insulin fibrillation and protect SK−N‐MC cells against amyloid toxicity [21] .…”

EGCG Promotes FUS Condensate Formation in a Methylation-Dependent Manner

“…The latter role of catechins in neuroprotection is of great interest as it counteracts the hallmark of NDs (formation of protein aggregates), which is thought to drive the process of neurodegeneration. Indeed, EGCG has been shown to directly interact with various amyloidogenic proteins, such as amyloid-β or α-synuclein, involving their low-complexity domains, thus inhibiting their propensity to form toxic aggregates [ 18 , 19 , 20 , 21 , 22 ]. Several amyloidogenic proteins harbor, in addition to their amyloidogenic domain (AD), regions rich in arginine and glycine residues (RG/RGG), and these regions contribute to their propensity to phase separate and possibly aggregate in (patho)physiological conditions [ 23 , 24 , 25 , 26 , 27 , 28 ].…”