Green Tea Epigallocatechin-3-gallate (EGCG) Targeting Protein Misfolding in Drug Discovery For Neurodegenerative Diseases Part 1

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. 

In den letzten Jahren haben Forscher herausgefunden, dass Targeting-Proteine möglicherweise an unserem Gedächtnis beteiligt sind. Targeting-Protein ist ein wichtiges intrazelluläres Protein, dessen Funktion vermutlich an der Signalübertragung zwischen Neuronen und der Gedächtnisbildung beteiligt ist. Daher ist das Verständnis der Beziehung zwischen gezielten Proteinen und dem Gedächtnis von großer Bedeutung für die eingehende Forschung zur Bildung des Gedächtnisses und zur Verbesserung des Gedächtnisses.

Untersuchungen zeigen, dass Anomalien in den Zielproteinen zu Problemen wie Gedächtnisstörungen und kognitivem Verfall führen können. Beispielsweise werden die Konzentrationen gezielter Proteine im Gehirn von Alzheimer-Patienten erheblich erhöht, was sich wahrscheinlich auf die Verbindungen und die Übertragung zwischen Neuronen und damit auf das Gedächtnis und die kognitiven Fähigkeiten auswirkt. Andere Studien haben gezeigt, dass mäßig aktive Targeting-Proteine dabei helfen, empfindliche neuronale Verbindungen zu fördern und das Gedächtnis und die kognitiven Fähigkeiten zu verbessern.

Wenn wir also unser Gedächtnis verbessern wollen, gibt es Möglichkeiten, einen moderaten Spiegel an gezielten Proteinen aufrechtzuerhalten. Halten Sie beispielsweise ein gewisses Maß an körperlicher Aktivität aufrecht, sorgen Sie für ausreichend Schlaf und Ernährung und führen Sie ein Training durch, um die kognitiven Fähigkeiten zu verbessern usw. Diese Methoden können uns dabei helfen, ein moderates Maß an gezielten Proteinen aufrechtzuerhalten und so unser Gedächtnis und unsere kognitiven Fähigkeiten zu fördern.

Kurz gesagt, die Beziehung zwischen gezielten Proteinen und dem Gedächtnis verdient unser tiefgreifendes Verständnis und unsere Erforschung. Wenn wir diesen Zusammenhang verstehen, können wir unser Gedächtnis und unsere kognitiven Fähigkeiten besser schützen und verbessern, was zu einem gesünderen, erfüllteren und glücklicheren Leben führt. Es ist ersichtlich, dass wir das Gedächtnis verbessern müssen, und Cistanche deserticola kann das Gedächtnis erheblich verbessern, da Cistanche deserticola ein traditionelles chinesisches Arzneimittel ist, das viele einzigartige Wirkungen hat, darunter die Verbesserung des Gedächtnisses. Die Wirksamkeit von Cistanche deserticola beruht auf den zahlreichen darin enthaltenen Wirkstoffen, darunter Gerbsäure, Polysaccharide, Flavonoidglykoside usw. Diese Inhaltsstoffe können die Gesundheit des Gehirns auf verschiedene Weise fördern.

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

1. Introduction

Neurodegenerative diseases (NDs) are a global public health threat and a huge financial burden for healthcare systems, not to mention a major hardship for society and families [1–3]. 

No effective treatment currently exists for NDs, and current therapies merely alleviate the symptoms. Thus, there is an urgent need for new, safer, and more effective drugs [4,5]. Natural products (NPs) and their unique polypharmacology provide significant advantages for drug discovery, particularly for the treatment of multifactorial and complex NDs [6–9]. 

The natural compound epigallocatechin-3-gallate (EGCG) has been extensively explored and studied for its therapeutic potential for NDs [10,11]. EGCG is a dietary polyphenol found in green tea with potent antioxidant and anti-inflammatory effects and an ability to modulate multiple targets implicated in the pathogenesis of many chronic diseases, including cancer, cardiovascular diseases, diabetes, and NDs [12]. 

The neuroprotective effects of EGCG have been reported for several NDs, including Alzheimer's disease (AD) and Parkinson's disease (PD), the two most common NDs [10,13]. 

The pathogenesis of NDs shares many fundamental processes associated with progressive neuronal dysfunction and death, with protein misfolding, oxidative stress, apoptosis, and neuroinflammation as some of them [14,15]. 

Meanwhile, EGCG has a multi-target mode of action (Figure 1) and synergistically acts against protein misfolding, oxidative stress, apoptosis, and neuroinflammation. Indeed, it is now recognized that the role of EGCG in ND management can be attributed to its antioxidant, anti-inflammatory, anti-apoptotic, and anti-amyloidogenic properties [16].

The pathological hallmark of many NDs is the accumulation of misfolded protein aggregates in the brain [17,18]. A growing body of evidence suggests that targeting protein misfolding is a promising strategy to prevent NDs. Protein misfolding and aggregation are principal causative factors in neurodegeneration, making their modulation a feasible target for ND prevention [17,19,20]. 

Protein misfolding and the consequent self-association into toxic oligomers and amyloid deposits are now considered central elements of the etiology of a wide range of NDs, including highly prevalent ones such as AD and PD, as well as rarer disorders such as prion diseases [21–23]. 

Although each ND is associated with abnormalities in the folding of a different protein, the molecular pathways leading to misfolding and aggregation appear to be similar. These findings suggest that a common therapy for NDs might be possible [24]. 

Studies have revealed that EGCG can interact with a variety of proteins linked to protein misfolding, such as Aβ, tau, α-synuclein (α-syn), transthyretin (TTR), and huntingtin [25–28]. 

This review addresses the contribution of EGCG research toward advances in neurodegenerative disease drug discovery. We begin by summarizing the available data of in-cell and animal ND models that support the therapeutic role of EGCG. We then focus on the protein misfolding as one of the most promising targets for ND treatment using EGCG.

2. Neurodegenerative Diseases

NDs are among the most widespread health problems, affecting millions of people worldwide [29]. Moreover, the number of individuals living with NDs such as AD and PD is increasing, negatively affecting families, communities, and healthcare systems worldwide [1,2]. 

These disorders are becoming highly prevalent, in part due to global increases in human life expectancy, since NDs are age-dependent disorders [30,31]. Indeed, aging is the primary risk factor for most NDs [32]. The impact of these diseases will further increase in the coming decades as humans live longer lives [31]. 

NDs are common chronic diseases typically characterized by a progressive loss of function and death of neurons in the brain or peripheral nervous system [15]. Although NDs differ in their clinical presentation, they do share several common pathological mechanisms, which are characterized by multiple targets. The underlying pathobiological processes are largely shared, with most involving the formation of abnormal protein deposits at their onset and all exhibiting a common and characteristic pattern of neuronal degeneration in anatomically or functionally related regions [14]. 

This idea that diverse NDs have a common cause and pathological mechanism supports that a common therapeutic strategy for these devastating disorders might be possible [24]. AD, PD, amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) are just a few examples of NDs that share similar biochemical reactions that lead to neurodegeneration [17,29,33]. 

Extensive evidence shows that misfolded proteins such as Aβ and tau in AD, α-syn in PD, and TAR DNA-binding protein 43 (TDP-43) in ALS participate in the formation, accumulation, and deposition of toxic misfolded aggregates [34–36]. Furthermore, protein misfolding (Table 1) is one of the principal causes of the onset and progression of NDs [17,21].

It has also been proposed that the overproduction of reactive oxygen species may have a complex role in promoting disease development [38,39]. In such cases, neurodegeneration results from the excessive production of free radicals induced by fragments of insoluble and/or overproduced misfolded proteins due to functional alterations in the mitochondria, inadequate energy supply, production of inflammatory mediators, and alteration of antioxidant defenses. Oxidative stress is, therefore, considered to be a common key player in the etiology and progression of these NDs [39,40]. 

Protein misfolding events can promote an excessive immune response causing neuroinflammation, which is also a common feature of NDs [41]. 

It is hypothesized that the release of protein aggregates from neurons activates microglia triggering an inflammatory response characterized by the liberation of inflammatory mediators, which contribute to disease progression and severity. 

For instance, in AD, the glial activation is followed by nuclear factor NF-kβ activation, synthesis, and release of proinflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, and IL-12 that affect neuronal receptors with an overactivation of protein kinases [41].

Neurodegeneration can, therefore, be seen as a consequence of several detrimental processes, including protein aggregation, oxidative stress, and neuroinflammation, which finally lead to the loss of neuronal functions and cognitive impairments [17,39,41]. 

Since NDs are multifactorial diseases related to complex pathophysiological characteristics and complicated interactions with a large number of genes and proteins, there is still no effective drug treatment for these conditions [42,43]. It is unlikely that targeting a single change will be effective at treating neurodegeneration, as several changes occur in the development of NDs. 

Given this multifactorial profile, NDs require a multi-target therapeutic approach, and current research is exploring multitarget drugs that can address more than a single event at the same time [44–47].

2.1. Alzheimer's Disease

AD is the most common ND worldwide and also the most common cause of dementia in elderly patients [2,3]. In 2019, AD and other forms of dementia were ranked by the World Health Organization (WHO) as the seventh most common cause of death in the world [48]. 

To date, only five drugs (tacrine, donepezil, rivastigmine, galantamine, and memantine) have been approved by the FDA to treat AD. The disease is currently incurable, with the available drugs only managing the symptoms and exhibiting severe side effects [42,49,50]. 

These drugs are based on a single-target strategy and focus on restoring neurotransmitter homeostasis. Finding disease-modifying AD therapies remains an urgent and unmet clinical need [5,51]. 

Since the approval of memantine in 2003, the first drug approved for AD was a marine-derived oligosaccharide, sodium oligomannate. With a mode of action related to gut microbiota and neuroinflammation, this latter compound was approved in 2019 in China for treating mild to moderate AD to improve cognition function [52,53]. 

AD is a multifactorial disease characterized by the progressive accumulation of Aβ fibrils and abnormal tau proteins in extracellular spaces and neurons, respectively, with associated neuron and synapse loss in multiple brain regions, especially in the frontal cortex and hippocampus [54,55]. 

The Aβ (Aβ40 and Aβ42 with 40 and 42 amino acids) and tau proteins (352 to 421 amino acids) have been identified as the key misfolded proteins in AD [56,57]. At the microscopic level, the brains of AD patients are characterized by the concurrent presence of two classes of abnormal structures: extracellular amyloid plaques and intraneuronal neurofibrillary tangles (NFTs). 

Both structures are made of highly insoluble, densely packed filaments. Distinct soluble building blocks form these structures: Aβ peptides for plaques and tau for NFTs [56]. 

The senile plaques and NFTs are recognized as the two major neuropathological hallmarks of AD [58–60]. As the major component of senile plaques, the Aβ peptide is considered to be a crucial factor that underlies neuronal and synaptic dysfunction in AD progression [61]. 

Hence, the amyloid hypothesis proposes Aβ as the principal cause of AD, suggesting that clinical symptoms such as memory loss and cognitive decline are caused by misfolding of the extracellular Aβ protein accumulates in senile plaques and also by intracellular deposition of misfolded tau protein [61–63]. In this context, Aβ has emerged as a promising therapeutic target in attempts to develop a disease-modifying treatment for AD. 

Most drugs tested for AD in the past 20 years have targeted the accumulation of the Aβ with a focus on decreasing levels of Aβ monomers, oligomers, aggregates, and plaques using compounds that decrease production, antagonize aggregation, or increase brain clearance of Aβ, such as β-site amyloid precursor protein cleaving enzyme 1 (BACE-1) inhibitors, and anti-Aβ antibodies [64–66]. 

Despite the large number of anti-Aβ drugs entering clinical development and the enormous expenditure on large and complex trials, these drug candidates have so far failed to show clinical benefits for AD [65]. 

It has, therefore, been suggested that the failure of drug discovery in AD reflects an incomplete understanding of disease mechanisms. Since Aβ has a physiological role, some anti-Aβ drugs that inhibit the production of 'nascent' Aβ, such as γ- secretase and BACE inhibitors, have been found to accelerate cognitive decline, possibly owing to off-target effects. 

It is speculated that more favorable outcomes might be achieved by targeting Aβ oligomers, the most neurotoxic molecular species, with encouraging results from monoclonal antibodies directed against these oligomers [66–69]. 

Notably, there has been a shift from an initial focus on amyloid plaques to a more contemporary view that memory failure in AD is caused by small soluble Aß oligomers acting as synaptotoxins, leading to cognitive impairment [70]. 

According to recent findings, Aβ oligomers play a key role in AD brain inflammation by activating the pro-inflammatory interleukin-1 (IL-1) receptors that mediate the alteration in levels of mitochondrial fission/fusion proteins, resulting in memory impairment [71].

2.2. Parkinson's Disease

PD is s considered to be the second most frequent ND in the world after AD [1,72]. It has been estimated that the global burden of PD more than doubled globally from 1990 to 2015 as a result of an aging population, with potential contributions from longer disease duration and environmental factors [1]. Studies in the area have implicated environmental and genetic risk factors in the pathogenesis of PD [73]. 

The environmental risk factors include pesticides and ambient air pollution [74–77]. PD is a progressive ND characterized by the selective loss of dopaminergic neurons in the substantia nigra pars compacta, located in the basal ganglia of the brain, resulting in the lack of dopamine in this organ [78–80]. 

Dopaminergic cell loss causes clinical signs and symptoms such as bradykinesia, rigidity, postural instability, and tremors [73]. So far, no cure has been available to treat PD, with pharmacological treatments mainly consisting of dopaminergic drugs, which are only therapies to reduce symptoms that are still limited by several side effects [81]. 

Most current drugs were approved for clinical use in the second half of the twentieth century, with the development of new drugs proceeding slowly since the FDA approval of levodopa in 1970. 

Levodopa remains the most effective drug therapy for the motor symptoms of PD, despite its long-term complications [82–84]. The pathological hallmark of PD is the presence of Lewy bodies within dopaminergic neurons in the brains of affected patients, and misfolded α-syn is known to be the principal component of Lewy bodies [85–88]. 

Although the formation of amyloid fibrils by α-syn aggregation plays a central role in the pathogenesis of PD, it has recently been shown that the formation of Lewy bodies-rather than fibrils-is one of the major drivers of neurodegeneration by disrupting cellular functions and inducing synaptic dysfunctions, as well as mitochondrial damage and deficits [89]. 

Several studies have shown that α-syn oligomers are the primary cause of neurotoxicity and play a critical role in PD, similar to that of Aβ oligomers in AD [90]. 

Emerging evidence suggests that small soluble α-syn oligomers are the most toxic species among the forms of α-syn aggregates and that size and topological structural properties are crucial factors for oligomer-mediated toxicity, involving the interaction with either neurons or glial cells [91].

2.3. Neurodegenerative Drug Discovery

Most NDs, including AD, PD, HD, and ALS, remain essentially incurable to date. As mentioned before, current therapy merely alleviates the symptoms but cannot stop the progress of the disease, highlighting the urgent need for more effective therapeutic strategies [4,5]. 

Barriers to the development of new drugs for NDs include an incomplete understanding of the biology of these multifactorial disorders, the presence of a blood-brain barrier (BBB) that restricts the flow of molecules to the brain, and a lack of clinically relevant animal models on which to test new drugs [92]. Although NDs are characterized pathologically by the aggregation of disease-specific misfolded proteins and changes in cellular stress responses, researchers remain focused almost exclusively on reducing the misfolded protein load (particularly that of Aβ in drug development for AD); however, outcomes have been disappointing [50,93]. 

Given the low success rate of ND drug discovery, a paradigm shift for innovative drug development strategies was required [94]. New treatments have been proposed, including ones that target various generic stress responses and preventative measures targeting the original misfolded protein triggers, their toxicity, and the spread of aggregates, which may hold promise for the future management of these diseases [93]. 

Ultimately, the drug discovery paradigm of NDs has gradually shifted from the design of selective drugs targeting a single pathophysiological pathway toward the development of multitarget agents directed at complex pathophysiological pathways of the diseases [44–47]. 

Indeed, the complexity and multiple etiologies of NDs make it challenging to obtain desirable therapeutic effects using single-target drugs. Therefore, multitarget-directed ligands have emerged in recent years as a powerful strategy to develop potential therapeutics for NDs [95–97]. 

NPs with multiple biological activities that can affect the pathophysiological changes in the brain that contribute to ND development and progression are of particular interest in anti-neurodegenerative drug discovery [98].

2.4. Natural Products Against Neurodegeneration

The use of phytotherapeutics continues to expand around the world, with many people now resorting to phytomedicine to treat and prevent a wide array of pathologies [99]. Many medicinal plants and their NPs have been reported as being able to alleviate the symptoms of NDs, including AD and PD [100–105]. Historically, NPs which are the most important sources of drugs may also hold promise for treating NDs [106,107]. 

Several medicinal plants contain active components that are known to possess antioxidant action [108,109]. Abundant data in the literature suggests that dietary NPs found in fruits and vegetables are powerful antioxidants that offer health benefits against several oxidative stress-induced NDs, including AD [110,111]. 

Most of these NPs have remarkable antioxidant properties and act mainly by scavenging free radical species [109,112]. Since oxidative stress has long been associated with neurodegeneration, there has been a significant increase in interest in finding natural and synthetic compounds with antioxidant and anti-inflammatory effects as promising drug candidates for treating NDs [113]. 

In recent years, several natural antioxidants have been exploited for their actual or supposed beneficial effect against oxidative stress, including flavonoids and polyphenols [114,115]. Likewise, plant-derived antioxidant polyphenols have come under the research spotlight due to their potential to prevent oxidative stress [109,112]. 

Several dietary phytochemicals with known antioxidant properties and anti-amyloidogenic effects have been investigated for their potential beneficial effects, including curcumin, resveratrol, and green tea catechins like EGCG [111]. 

In particular, green tea catechins have been highlighted as having potential protective effects against NDs due to their diverse array of physiological actions, which include potent antioxidant effects [116,117]. 

Notably, because of their broad spectrum of pharmacological and biological activities, NPs are considered promising alternatives for treating neurodegeneration as they might play a role in ND drug development and discovery [118–121]. 

NPs remain a promising pool for discovering scaffolds with high structural diversity and various bioactivities that can be directly developed or used as starting points for optimization into novel drugs [122]. 

Many of these NPs are known as multi-targeted compounds as they alter multiple pathways at the molecular level, making them ideal therapeutic options for multifactorial and complex diseases such as NDs [7]. MPs have, therefore, emerged as potential multi-targeted agents for treating NDs. The major mechanisms through which NPs exert their neuroprotective effects include antioxidant, anti-inflammatory, antithrombotic, antiapoptotic, and neurotrophic activities, as well as acetylcholinesterase and monoamine oxidase inhibition [123]. 

Among neuroprotective NPs, phenolic molecules are of particular interest since most can target both amyloid aggregation and oxidative stress, as confirmed by numerous studies with phenolic compounds such as EGCG, curcumin, resveratrol, quercetin, and oleuropein [123–126]. Evidence also exists that some of these NPs suppress the neurotoxicity of the most toxic oligomer species [127–131]. 

Finally, targeting protein misfolding with different NPs has been recognized as one of the most promising therapeutic strategies against NDs since many NDs involve the misfolding and aggregation of specific proteins into abnormal, toxic species [125,132]. 

Therefore, the use of small molecules to stop, slow, or reverse the protein misfolding and aggregation process may be a valuable approach to reduce neurodegeneration [17,20]. 

Concerning the molecular mechanisms by which NPs target misfolded proteins, it is likely that they interfere with electrostatic and hydrophobic interactions which stabilize β-sheets due to the establishment of intermolecular interactions with sidechain or backbone residues of the protein. 

These intermolecular interactions might be covalent and non-covalent such as hydrogen bonding, π-π interactions, or charge-charge interactions [132].

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