Epigallocatechin-3-Gallate (EGCG): New Therapeutic Perspectives For Neuroprotection, Aging, And Neuroinflammation For The Modern Age Part 2

In light of these facts, the therapeutic strategies are mostly symptomatic treatments with non-steroidal anti-inflammatory drugs (NSAIDs) shown to decrease the risk of AD and delay progression, but only in prospective observational studies by halting cyclooxygenase 2 (COX-2) or the prostaglandin E2 receptor, activating phagocytosis by microglia, triggering peroxisome proliferator-activated receptor gamma (PPAR-γ), and selective decrease of Aβ42 [19]. 

In recent years, people have paid more and more attention to protecting their memory. Many people believe that long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) may hurt memory. However, existing research suggests this concern may be unwarranted.

NSAIDs are a class of drugs widely used to relieve pain, fever, and inflammation, such as aspirin, ibuprofen, and naproxen. They work by blocking an enzyme in the body, which in turn reduces the inflammatory response. Some early research suggested that these drugs may have some negative effect on memory, but existing large-scale randomized controlled trials have not found this effect.

In a multinational study, researchers examined the relationship between oral NSAIDs and the risk of cognitive impairment. They studied 2,721 people aged 65 to 96, who took cognitive ability tests for five consecutive years. The results showed that oral NSAIDs, especially pain-relieving drugs, were associated with lower cognitive risks. In contrast, when the researchers analyzed learning inhibitors and other analgesics separately, no significant correlations were found.

The researchers pointed out that due to the therapeutic effects of NSAIDs, long-term use of these drugs may reduce the risk of patients suffering from chronic inflammatory diseases. Inflammation is associated with decreased brain function, so NSAIDs may help protect memory by reducing inflammation. Furthermore, in this study, researchers did not find an association between NSAIDs and the risk of Alzheimer's disease or other dementias.

Overall, scientific research has not fully confirmed the negative relationship between NSAIDs and memory. If you take long-term oral NSAIDs to relieve physical discomfort, you don't have to worry about adverse effects on your memory. However, we still recommend that you contact your doctor and follow your doctor's advice when using this type of medication. When it comes to protecting our memory, it is equally important to adhere to a healthy lifestyle and establish positive habits, such as maintaining appropriate exercise every day, eating a reasonable diet and social activities, improving self-awareness, and learning new skills, etc. Let's protect and develop our memory skills together. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidation and inflammatory reactions in the brain, thereby protecting the health of the nervous system. In addition, Cistanche deserticola can also promote the growth and repair of nerve cells, thus enhancing the connectivity and function of neural networks. These effects can help improve memory, learning, and thinking speed, and may also prevent the development of cognitive dysfunction and neurodegenerative diseases.

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The Food and Drug Administration (FDA) approved acetylcholinesterase inhibitors (AChEI) (rivastigmine and donepezil) and NMDA receptor antagonist (Memantine) drugs have been utilized to alleviate the cholinergic and glutamatergic disintegration/excitotoxicity, respectively, leading to synaptic disruption caused by the AD pathology [32–34]. Present therapeutics are disease-modifying agents mainly focused on the Aβ propagation, but they have failed in clinical trials [35]. 

Other targeted strategies are sirtuins (SIRT), which have recently been associated with age-related diseases, and caspases, which are involved in apoptosis and autophagy [36]. Recently, more studies have focused on preventing the risk factors and co-morbidities, in particular, diet and obesity [37], cerebrovascular (the brain renin-angiotensin system (RAS) [38]), and energy dysregulation [39].

2.3. Protein Aggregation in AD: The Role of Amyloid Beta (Aβ)

Extensive research has linked APP with AD pathogenesis [40]. The adhesion to APP occurs in two unique ways: α-secretase, a proteolytic enzyme that triggers the nonamyloidogenic pathway, which leads to APP joining within the Aβ region, resulting in Aβ generation. Adherence of APP by α-secretase generates α-secreted APP (sAPPα) and the leftover fragment C terminal (α-CTF). 

The other route involves the BACE-catalyzed β-attachment of APP promoting Aβ formation and the amyloidogenic pathway. BACE cleavage produces β-secreted APP (sAPPβ) and the c-terminal fragment β-CTF of APP. The c-terminal remnants (α and β CTF) are substrates for γ-secretase, a universal multimeric protease. The binding of α-CTF to γ-secretase yields a shortened nonamyloidogenic peptide (p3). 

However, β-CTF adherence promotes Aβ propagation. Aβ is evidence of the main proteinous remnant of amyloid plaques in the AD brain [41]. The APP intracellular domain (AICD) is generated in both the amyloidogenic and nonamyloidogenic pathways via the joining of γ-secretase. Most amyloid-beta remnants are Aβ40 in length; however, the elongated Aβ 42 variant is the most pathogenic. 

A possible inference is that the continuous assembly of Aβ oligomers causes synaptic damage culminating in neurodegeneration [3]. The latest research has shown that Aβ can activate microglia and promote a chronic inflammatory state resulting in unregulated proinflammatory cytokine release, leading to neurodegeneration [42,43]. 

Alasmari et al. [40] demonstrated that proinflammatory cytokines could mediate Aβ neurotoxicity via APP protein homeostasis/metabolism. Aβ has also been linked to causing iron dyshomeostasis, stimulating oxidative stress in microglia leading to neurodegeneration [44,45].

2.4. Tau Protein: Neurofibrillary Tangles and Aggregation in AD

Tau is related to a family of microtubule-associated proteins (MAPs) that reside mainly in neurons, function to support microtubules, and aid in proper cellular trafficking and cytoskeleton scaffolds for cells. Tau protein contributes to the formation of neurofibrillary tangles due to impaired oxidative phosphorylation or apoptotic function [46]. 

Tau becomes pathological due to hyperphosphorylation that occurs due to unstable kinase and phosphatases acting on the tau protein [47]. The phosphorylation of tau has been associated with N methyl D aspartate receptor (NMDAR) at postsynaptic locations, which may be related to the synaptic instability that occurs in PD [48]. 

The mechanism of filament aggregation that occurs in tau is still being investigated. The process of fibrillogenesis (similar process to Aβ fibrillogenesis) has been postulated as one of the mechanisms. 

First, protein dimerization occurs through the arrangement of disulfide bridges or ionic bonds; then, a nucleation phase follows, in which the dimers self-assemble to generate oligomers; lastly, the elongation phase occurs in which the oligomers thicken. 

Tau autosomal dominant mutations in microtubule-associated protein (MAPT), the gene encoding for tau, were found to cause frontotemporal dementia with parkinsonism (FTPD-17 mutation) [49].

3. Role of Inflammation

Current research has led to neuroinflammation as being a prominent factor in the genesis of neurodegeneration. The innate immune response to viral infection or traumatic brain injury induces glial cell activation, i.e., microglia and astrocytes, essential for immunoregulative central nervous system (CNS) homeostasis [50]. 

This regulation is carried out in a series of processes conjunctionally between the microglia and astrocytes, leading to neurodegeneration at various molecular intervals involving cell death mediation, synaptic remodeling, as well as immune-signaling regulation, i.e., (a) apoptosis, (b) necroptosis, (c) autophagy, (d) retrograde degeneration, (e) Wallerian degeneration, (f) demyelination, and (g) astrogliopathy [51].

The complement system serves as a pivotal pathway for regulating the interplay of acute vs. chronic neuroinflammation within the CNS microenvironment and links to understanding CNS immunoregulation [52–54]. 

Neuroinflammation is normally beneficial for the proper control of external stressors. Still, it can become detrimental when the immune response is prolonged (or chronic) due to immunosenescent aging, which leads to immune signaling dysregulation culminating in neurodegenerative pathogenesis [55,56]. 

De Oliveira et al. [57] discuss the disruption of natural energy (mitochondrial) homeostasis by the mitochondrial damage-associated molecular patterns (mDAMPs), which can lead to receptor-mediated (NOD-like receptor (NLR) and TLR) cascade of inflammatory immunological response. Continued research is focused on the relationship between chronic inflammation and AD.

3.1. Microglia and the Debilitating Effects Caused by Aging

Microglia are specialized macrophages of the CNS. Microglia function in the surveillance of the CNS microenvironment through six divisions: (1) proliferation, (2) morphological transformation, (3) motility and migration, (4) Intercellular communication, (5) phagocytosis, and (6) proteostasis. Microglia differ from other glial cells, such as astrocytes, by their hematopoietic origin and main response to pathogen infection and injury [58]. 

Microglia contain many macrophage-associated markers, i.e., CD11b and CD14. These cells are activated by either the classical or alternative complement system; classically, microglia become activated due to pathogen invasion and initiate the major histocompatibility complex II (MHC-II), which recruits T cells and other proinflammatory mediators. 

They also contain many receptors that function in surveillance, such as the pattern recognition receptors (Tolllike receptors (TLRs)), retinoic acid-inducible gene-I-like receptors (RIG-1 like receptors), and nucleotide-binding oligomerization domain-like receptors (NOD-like receptors). 

Protein recognition receptors (PPRs) sense pathogen recognition molecular patterns (PAMPs), whereas TLRs detect damage-associated molecular patterns (dAMPs) [59,60]. In AD, progression seems to render microglial cells less efficient in degrading these dense aggregates [61]. 

Microglia also contain many other receptors, such as ion channels, that aid in microglial recognition of disease-associated molecular patterns (DAMPs) expelled from damaged or necrotic cells and serve a role in the clearance of debris and stimulation of tissue repair after CNS injury, such as purinergic receptor and receptor for advanced glycation end products (RAGE). 

The purinergic P2 purinoreceptors are categorized into two subgroups: ionotropic receptors (P2X receptors), which create ion channels that are opened by adenosine triphosphate (ATP), and metabotropic receptors (P2Y receptors), which bind purines or pyrimidines and initiate downstream signaling events through G-protein coupled receptors (GPCRs) [62]. 

Nucleoside triphosphates (NTPs) expelled from injured cells can attach to P2X or Y receptors and stimulate the pro-inflammatory transcription mediators via the transcription factor, nuclear factor kappa B (NF-κB), and activator protein I (AP1). Microglia have also been shown to crosstalk with astrocytes and intensify the immune response. Microglia is a crucial factor in neurovascular maturation and is involved in angiogenesis [63]. 

This role has allowed for extensive research in its association with various diseases related to the brain, such as ischemic stroke, brain tumors, and neurodegenerative disorders.

 Aging causes a gradual reduction in physiological functions and behavioral capabilities, which is displayed at many phases of the organism, especially in the CNS [64]. Microglia experience many age-related transformations that advance to promoting a chronic mild inflammatory environment, i.e., elevated production of inflammatory cytokines and ROS. Research has shown that the normal brain mass atrophies 2–3% per decade after 50 [64]. 

Using magnetic resonance technology (MRT) and voxel-based morphometry, atrophies were present mainly in the gray and white matter volume changes in the prefrontal, parietal, and temporal areas. Furthermore, complex learning functions are diminished with age. At the cellular level, aging leads to shrinking telomeres and initiation of tumor suppressor genes, compiling DNA damage, oxidative stress, and imbalance of pro- and inhibitory inflammatory cytokine activity. 

Mosher and Coray [65] made the important statement, "The hallmarks of microglial aging may also sometimes be characterized as dysfunctional and even hyper-reactive responses." It has been postulated that cumulative stimulation in response to systemic infections throughout a lifetime leads to systemic inflammation, causes the cells to be hyperactivated, and aids in neurodegeneration. 

In addition, an increase in the engineering of ROS via permeability of the blood-brain barrier (BBB) leads to the deterioration of neurons and other brain cells and heightened systemic inflammation [65].

Research has shown that microglia proliferation and self-renewal increases with age. 

Still, it is believed that this progressive assembly of microglia is a compensatory mechanism to sustain the necessary level of protection from the overall microglial population as the individual cells become less capable with age [65]. Morphological changes in AD show that microglia have short, thick, and poorly ramified processes [65]. Microglial motility is reduced with age and displays diminished reactions to exogenous ATP and laser-induced focal tissue injuries. 

Aged microglia display overexpression of many pro-inflammatory markers, such as MHCII, antigens, CD11b/CR3, and CD14. It has also been shown that normal mediators of microglial activation and inflammatory responses are curtailed due to aging [66]. 

Microglia normally modulate the phagocytotic processes involved in the immune system. Still, aging diminishes these processes as evidenced in dysregulated proteostasis pathways that involve a disruption in chaperone-mediated protein folding and stability, protein trafficking, protein breakdown, autophagy, and compiling of proteins in AD [65].

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