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Review
. 2023 Jul 20;12(7):1460.
doi: 10.3390/antiox12071460.

Alzheimer's Disease and Green Tea: Epigallocatechin-3-Gallate as a Modulator of Inflammation and Oxidative Stress

Víctor Valverde-Salazar  1 , Daniel Ruiz-Gabarre  1 , Vega García-Escudero  2   3
Affiliations
Review

Alzheimer's Disease and Green Tea: Epigallocatechin-3-Gallate as a Modulator of Inflammation and Oxidative Stress

Víctor Valverde-Salazar et al. Antioxidants (Basel). .

Abstract

Alzheimer's disease (AD) is the most common cause of dementia, characterised by a marked decline of both memory and cognition, along with pathophysiological hallmarks including amyloid beta peptide (Aβ) accumulation, tau protein hyperphosphorylation, neuronal loss and inflammation in the brain. Additionally, oxidative stress caused by an imbalance between free radicals and antioxidants is considered one of the main risk factors for AD, since it can result in protein, lipid and nucleic acid damage and exacerbate Aβ and tau pathology. To date, there is a lack of successful pharmacological approaches to cure or even ameliorate the terrible impact of this disease. Due to this, dietary compounds with antioxidative and anti-inflammatory properties acquire special relevance as potential therapeutic agents. In this context, green tea, and its main bioactive compound, epigallocatechin-3-gallate (EGCG), have been targeted as a plausible option for the modulation of AD. Specifically, EGCG acts as an antioxidant by regulating inflammatory processes involved in neurodegeneration such as ferroptosis and microglia-induced cytotoxicity and by inducing signalling pathways related to neuronal survival. Furthermore, it reduces tau hyperphosphorylation and aggregation and promotes the non-amyloidogenic route of APP processing, thus preventing the formation of Aβ and its subsequent accumulation. Taken together, these results suggest that EGCG may be a suitable candidate in the search for potential therapeutic compounds for neurodegenerative disorders involving inflammation and oxidative stress, including Alzheimer's disease.

Keywords: Alzheimer’s disease; EGCG; amyloid β; antioxidant; green tea; neuroprotection; tau.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Amyloid β and tau pathology in Alzheimer’s disease. The main hallmarks of an AD brain are the accumulation of extracellular amyloid-β senile plates (1), the accumulation of intracellular neurofibrillary tangles of tau (2) and neuronal death (3). The areas in which these three features coexist are called neuritic plates (4). Amyloid precursor protein (APP) processing can take place through the amyloidogenic pathway (A), being cleaved by β-secretase (BACE), generating the sAPPβ and CTFβ fragments. The latter is subsequently processed by γ-secretase, generating Aβ42 and Aβ40, which induce amyloid β pathology in an AD brain (5) that ultimately affects neuronal homeostasis and induces cell death (6). On the contrary, in the non-amyloidogenic pathway (B), APP is cleaved by α- and γ-secretases, generating CTFα and sAPPα fragments that exert a neuroprotective function because a diminished APP conversion to Aβ and sAPPα inhibits BACE (7). On the other hand, tau is a microtubule-associated protein that establishes their structure. Post-translational modifications of tau, including phosphorylation, induce the detachment of tau and microtubule destabilization (8) and lead to tau aggregation (9). The accumulation of tau protein causes a failure of neuronal homeostasis whose final consequence is neuronal death (10).
Figure 2
Figure 2
Oxidative stress in Alzheimer’s disease. There is an increase in oxidative stress in an AD brain, which induces hyperphosphorylated tau (1) and amyloid-β (2) accumulation, mitochondrial dysfunction (3) and inflammation (4). At the same time, these processes also induce oxidative stress, generating a vicious cycle. Mitochondrial dysfunction is related to Aβ accumulation and, at the same time, Aβ is able to impair mitochondrial function (5). The accumulation of Aβ also induces tau hyperphosphorylation (6), which provokes mitochondrial dysfunction (7). Either Aβ (8) or tau (9) accumulation induce inflammation, which, in the same way, favours the accumulation of Aβ and tau. The accumulation of metals is one of the main causes of ROS increasement (10) in an AD brain and it also favours Aβ pathology (11) and inflammation processes (12). All these features together induce the loss of neuronal connections and the reduction in neurons shown in an AD brain (13). Ferroptosis is increased in an AD brain due to increased levels of iron, ferririn and transferrin and diminished ferroporter and GPX4 (14) that causes neuron necroptotic death and subsequent inflammation (15). EGCG is able to block oxidative stress (16) and, thanks to its chelating activity, it counteracts the accumulation of heavy metals (17) and ferroptosis (18), protecting the brain from all these harmful effects.
Figure 3
Figure 3
Antioxidant activity of EGCG. The antioxidant compound EGCG binds to antioxidant regulatory elements (ARE), inducing the expression of stress response genes (1) such as haem oxygenase (2) and glutathione-S-transferase (3) enzymes, counteracting oxidative stress processes (4). Additionally, EGCG enhances the activity of SOD and catalase (5), which reduce oxidative stress (4). Thanks to its hydroxyl groups, EGCG harbours chelating properties (6) that exert antioxidant activity, promoting neuroprotective effects (7). Also, EGCG can inhibit the production of ROS/RNS and 3-Hydroxykynurenine effect due to this antioxidant capacity (8), avoiding oxidative stress (9).
Figure 4
Figure 4
Effect of metal chelation mediated by EGCG in Alzheimer’s pathology. In an AD brain, iron accumulation promotes amyloidogenic processing (1), increasing Aβ40/Aβ42 levels (2), leading to the accumulation of Aβ (3). Moreover, brain iron accumulation produces an increase in tau hyperphosphorylation (4) that results in microtubule destabilization and the accumulation of tau protein (5). As a consequence, iron produces neurodegeneration (6). The metal chelator activity of EGCG (6) inhibits iron accumulation in the brain (7), therefore diminishing the accumulation of Aβ (8) and tau protein (9). Moreover, EGCG can directly potentiate the expression of p21 (10) and p27 (11), while diminishing the expression of cyclin D1 (12) and pRB (13), abolishing cell cycle re-entry (14). On the other hand, EGCG can promote the activation of HIF-1α (15), inducing the expression of cell survival genes (16). EGCG promotes the production of SAPPα (17) and the non-amyloidogenic processing of APP (18), generating neuroprotection effects (19).
Figure 5
Figure 5
Modulation of PKC-mediated pathways by EGCG in Alzheimer’s disease. EGCG can induce the activation of PKC pathways (1), specifically the isoform PKCζ (2) that enhances long-term memory (3), PKCα (4) that results in an increase in memory function (5) and PKCε (6) that activates BDNF factor (7), promoting synaptogenesis (8), neuronal survival (9), Ca2+ liberation (10) and changes of synaptic structures (11), altogether promoting neuroprotection (12). The generation of Aβ produces Aβ plaques (13), promoting neurodegeneration processes (14). Aβ also inhibits the PKC pathway (15) and RACK (16), whose receptors are required to activate PKC (17), and blocks BDNF (18). Moreover, the isoforms PKCα and PKCε activate α-secretase (19), promoting the generation of sAPPα (20) that inhibits Aβ production (21). PKCε activates ECE1 (22), which degrades Aβ (21). The activation of the PKC pathway inhibits GSK3β (23), which is involved in tau hyperphosphorylation (24) that finally leads to neurodegeneration processes (14). EGCG produces the reduction in protein Bax (25) and promotes the degradation of protein Bad (26) through the proteasomal system (27).
Figure 6
Figure 6
Modulation of MAPK pathway by EGCG in Alzheimer’s disease. Upon oxidative stress, EGCG induces antioxidant defences with the activation of the Keap1/Nrf2/ARE pathway (1) and increases ERK1/2 (2), promoting cell survival (3) and neuroprotective effects (4). Conversely, EGCG inhibits the ERK (5), p38 (6) and JNK (7) pathways whose effects contribute to mitochondrial disfunction and altered dynamics (8), induce tau protein hyperphosphorylation and aggregation (9) and increase apoptosis (10) and inflammation (11), leading to cell death (12). Therefore, EGCG can avoid this cell death (13).
Figure 7
Figure 7
Modulation of PI3K/Akt pathway mediated by EGCG. Akt/protein kinase B (PKB) is activated by Phosphatidyl Inositol 3 Kinase (PI3K) (1), which catalyses the conversion of phosphatidyl inositol (4,5) biphosphate (PIP2) into phosphatidyl inositol (3,4,5) triphosphate (PIP3), a process that is reversed by phosphatidylinositol (3,4,5)-triphosphate 3-phosphatase (PTEM) (2). PIP3 also recruits phosphoinositide-dependent kinase 1 (PDK1) to the plasma membrane, activating Akt (3). Akt phosphorylates glycogen synthase kinase 3 (GSK3), inhibiting its function (4). Active GSK3 is able to phosphorylate Mcl-1 (5), which is targeted for proteasomal degradation (6), liberating Bax and Bak proapoptotic factors (7). This causes the permeabilization of the mitochondrial outer membrane, releasing cytochrome c (Cyt C) (8) that attaches to Apaf-1, generating the apoptosome (9), leading to the activation of caspase 3 (10) that induces apoptosis (11). GSK3 also phosphorylates tau, inducing its aggregation and subsequent neurodegeneration (12). EGCG can ultimately increase PI3K and Akt activity (13) and inhibit PTEM in the presence of ROS (14), inhibiting apoptosis (15), phospho-Tau aggregation (16) and, therefore, generating neuroprotection.
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