Epigallocatechin-3-Gallate (EGCG): New Therapeutic Perspectives for Neuroprotection, Aging, and Neuroinflammation for the Modern Age

Abstract

Alzheimer's and Parkinson's diseases are the two most common forms of neurodegenerative diseases. The exact etiology of these disorders is not well known; however, environmental, molecular, and genetic influences play a major role in the pathogenesis of these diseases. Using Alzheimer's disease (AD) as the archetype, the pathological findings include the aggregation of Amyloid Beta (Aβ) peptides, mitochondrial dysfunction, synaptic degradation caused by inflammation, elevated reactive oxygen species (ROS), and cerebrovascular dysregulation. This review highlights the neuroinflammatory and neuroprotective role of epigallocatechin-3-gallate (EGCG): the medicinal component of green tea, a known nutraceutical that has shown promise in modulating AD progression due to its antioxidant, anti-inflammatory, and anti-aging abilities. This report also re-examines the current literature and provides innovative approaches for EGCG to be used as a preventive measure to alleviate AD and other neurodegenerative disorders.

Keywords: Alzheimer’s disease (AD); aging and epigallocatechin-3-gallate (EGCG); inflammation; microglia; oxidative stress.

Figure 1

Common etiological factors that might lead to neurodegeneration. The etiological origins of neurodegenerative diseases such as AD are unknown, but the known stimulators are multifactorial, i.e., genetic, environmental, aging, and molecular. AD displays the typical characteristics associated with neurodegeneration: protein misfolding provoking protein aggregation, synaptic dysfunction, metal toxicity, mitochondrial dysfunction, and ROS.

Figure 2

Chemical Structure of EGCG and its progenitors. The chemical makeup of EGCG contributes to its ROS reducing and anti-inflammatory properties. EGCG comprises 4 rings denoted A, B, C, and D. A and C form the benzopyran ring, which has a phenyl group at C2 and a gallate group at C3. The B ring has positional 3, 4,5-trihydroxyl groups, and the D ring galloyl moiety (gallate group) is configured as an ester at C3. The B and D rings have contributed to their ROS deactivating properties. The D ring has been shown to be associated with anti-inflammation and anticancer characteristics.

Figure 3

Medicinal Properties of Green Tea polyphenols. Extensive research has shown that green tea polyphenols exhibit anti-inflammatory, antioxidative, and anti-microbial attributes, preventing or alleviating many terminal diseases, such as cardiovascular disease, neurodegenerative diseases, and osteoporosis.

Figure 4

Proposed mechanism of EGCG autophagic response. Autophagy is a molecular recycling system explored extensively in cancer research. The promotion of molecular insults, i.e., ER stress, hypoxia, and chemotherapy, initiate the AMPK or MAPK/AKT/mTOR pathway, which recruits downstream effector protein kinases Unc-51 like autophagy activating kinase (ULK1/2,) and RP200 leading to the cascade of events leading to degradation of cellular debris. EGCG can act via AMPK or MTORC1 and act indirectly on autophagic-like proteins (ATG9) and ATG-9-15 to induce the autophagic series of events resulting in cellular debris breakdown and leading to the residue being reused for proper cellular growth and homeostasis.

Figure 5

Contributing factors of cholesterol biosynthesis to AD genesis and possible inhibition by EGCG. (A) the normal cascade of events involves converting acetyl coenzyme A (Acetyl CoA) to 3-hydroxy-3-methylglutaryl-CoA by hydroxymethylglutaryl-CoA (HMG-CoA) synthase, which is changed to mevalonate by HMG-CoA reductase. A succession of enzymatic reactions converts mevalonate into 3-isoprenyl pyrophosphate, farnesyl pyrophosphate, squalene, lanosterol, and cholesterol leading to the generation of the oxysterol 27-hydroxycholesterol due to the enzymatic action of cholesterol 24S-hydroxylase (CYP46). The high amounts of oxysterols, i.e., 27 hydroxycholesterols (27-OHC the role), can contribute to AD biogenesis. (B) EGCG acting similar to a statin may be able to negate this elevation by inhibiting the regulative enzyme HMG-COA reductase, which will reduce the production of the oxysterols by preventing the enzymatic conversion of mevalonate resulting in the prevention of AD.

Figure 6

Picture Summary of EGCG highlights of this paper. Picture summary of key medicinal actions of EGCG as discussed in this review article.