Green Tea Epigallocatechin-3-gallate (EGCG) Targeting Protein Misfolding in Drug Discovery for Neurodegenerative Diseases

Abstract

The potential to treat neurodegenerative diseases (NDs) of the major bioactive compound of green tea, epigallocatechin-3-gallate (EGCG), is well documented. Numerous findings now suggest that EGCG targets protein misfolding and aggregation, a common cause and pathological mechanism in many NDs. Several studies have shown that EGCG interacts with misfolded proteins such as amyloid beta-peptide (Aβ), linked to Alzheimer's disease (AD), and α-synuclein, linked to Parkinson's disease (PD). To date, NDs constitute a serious public health problem, causing a financial burden for health care systems worldwide. Although current treatments provide symptomatic relief, they do not stop or even slow the progression of these devastating disorders. Therefore, there is an urgent need to develop effective drugs for these incurable ailments. It is expected that targeting protein misfolding can serve as a therapeutic strategy for many NDs since protein misfolding is a common cause of neurodegeneration. In this context, EGCG may offer great potential opportunities in drug discovery for NDs. Therefore, this review critically discusses the role of EGCG in NDs drug discovery and provides updated information on the scientific evidence that EGCG can potentially be used to treat many of these fatal brain disorders.

Keywords: Alzheimer’s disease; Parkinson’s disease; amyloid-β; anti-amyloidogenic; anti-neurodegenerative; catechins; epigallocatechin-3-gallate; misfolded proteins; natural products; neuroprotective; α-synuclein.

Figure 1

Schematic showing the role of epigallocatechin-3-gallate (EGCG) in neuroprotection. Neurodegeneration is a multifactorial process, and preclinical models have shown that EGCG exerts neuroprotective effects through several mechanisms.

Figure 2

Schematic representation showing that neurodegenerative diseases (NDs) share their origin in protein misfolding followed by the formation of β-sheet-enriched structures. These protein misfolding events are the molecular alterations that trigger several NDs. 3D structures of monomers and fibrils retrieved in the protein data bank (PDB). Aβ monomer (PDB code: 1IYT); α-syn monomer (PDB code: 1XQ8); murine cellular prion protein (PDB code: 1AG2); Aβ fibril (PDB code: 5KK3); α-syn fibril (PDB code: 2N0A); prion protein fibril (PDB code: 6UUR). The protein structures here shown were obtained from recombinantly expressed proteins in vitro, except for Aβ monomer, a chemically synthesized peptide.

Figure 3

Schematic representation of the amyloid aggregation process. (A) Aggregation kinetics of misfolded proteins: the sigmoidal curve represents the temporal evolution of a fluorescent signal. (B) Under pathological conditions, natively unfolded monomers are able to self-aggregate in pathological oligomers (primary nucleation). Thus, oligomers can be extended into protofibrils (secondary nucleation) and mature fibrils.

Figure 4

Schematic illustration showing the effect of EGCG on α-syn aggregation. EGCG induces the formation of two distinctive types of α-syn oligomers. The accelerated amyloid fibril formation is also observed in the presence of EGCG.