Epigallocatechin-3-Gallate (EGCG): New Therapeutic Perspectives For Neuroprotection, Aging, And Neuroinflammation For The Modern Age Part 3
Apr 22, 2024
3.2. Microglia and Tau
The senescence of microglia manifests itself as morphological alterations, cytokine expression, phagocytosis, stimulation, and density [67]. Ongoing inquiry shows that microglia may be responsible for the synaptic and non-synaptic circulation of pathological tau.
In recent years, more and more scientific studies have confirmed the close relationship between cytokine expression and memory. Cytokines are signaling molecules that can stimulate or inhibit the body's immune system response. They can also affect the transmission of information between neurons in the brain. Studies have found that the expression levels of certain cytokines are closely related to the improvement of memory.
For example, a study published in the journal Nature found that a protein in the brain called BDNF can promote connections between neurons and enhance memory. BDNF levels are affected by many factors, including exercise, diet, sleep, and social activities. Research shows that people who participate in these activities are more likely to maintain higher BDNF levels, making it easier to maintain good memory.
In addition, inflammatory responses can also affect memory. A study published in the journal Cell shows that an inflammatory response in the brain can cause connections between neurons to become unstable, affecting memory. Therefore, maintaining a healthy lifestyle and controlling the body's inflammatory response are also important ways to maintain good memory.
In conclusion, there is a close and important relationship between cytokine expression and memory. We should actively participate in activities such as exercise, diet, sleep, and social interaction while paying attention to controlling the body's inflammatory response to maintain high cytokine levels and thus have better memory. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors. These substances are very important for memory and learning. In addition, Cistanche deserticola can also improve blood flow and promote oxygen delivery, which can ensure that the brain receives sufficient nutrients and energy, thereby improving brain vitality and endurance.
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Microglia envelop both soluble and insoluble states of tau. The envelopment of tau allows for
either tau degradation or release in exocytosing microvesicles known as exosomes in which
elevated levels are situated in the CSF and blood of AD patients [68]. Further postulation is
that dephosphorylated tau contributes to microglial neurotoxicity [69].
4. Neuroinflammatory Mediators
Cognitive disruption due to cytokine/chemokine-regulated associations between CNS neuronal bodies has been thoroughly researched [70]. AD pathology leads to the overexpression of these mediators resulting in enhanced plaque formation and neuronal cell deterioration [70].
Inflammatory regulators involved in AD are as follows: (1) tumor necrosis factor-alpha (TNF-α), (2) interleukin (IL)-6, (3) interferon-gamma (IFN)-γ, (4) inducible protein-10 (CXCL10), (5) monocyte chemoattractant protein 1 (MCP-1), and (6) C-X-C motif ligand (CXCL-8). Interleukin 6 (IL-6) regulates numerous immune reactions affecting CNS cell development and cellular diversity by cooperating with precise soluble or membrane-bound receptors [30].
IL-6 has been shown to have a myriad of inflammatory regulative properties [71], but it can also stimulate acute phase proteins leading to enhanced vascular permeability, lymphocyte provocation, and antibody creation. IL-6 activation by nuclear factor kappa B (NF-κB) modulates vascular inflammation [72]. TNF-α is another proinflammatory cytokine that has been linked to many neurological disorders.
Mice studies have displayed enhanced neuronal loss after lesioning due to the lack of the TNF receptor compared to normal TNF receptor-adequate mice. Additional studies have shown that TNF-α instigates the presence of protective molecules, such as manganese superoxide dismutase (MnSOD) [73–75]. New investigations have shown TGF-βs raise APP expression in cultured astrocytes and microglia and apolipoprotein-E (ApoE) formation in brain slice culture [30].
Chemokines of the CXC or alpha (α) subfamily consist of positionally conserved cysteine residues at the amino terminus divided by a single amino acid allowing for chemo-taxis of neutrophils and endothelial cells (IL-8). Chemokines direct biological responses via seven-transmembrane G-protein coupled cell surface receptors (GPCRs). CXC Motif ligand 12 is involved in neurogenesis and mobilizes neurological bodies to sites of lesions in the CNS [76].
Macrophage migration inhibitory factor (MIF) is a pleiotropic proinflammatory cytokine that enhances the creation of other inflammatory cytokines and is localized in microglia. Research has demonstrated that MIF attaches to Aβ in AD-compromised areas [76].
Macrophage inflammatory protein 1 (MIP-1α) expression is in numerous neurological and immunological areas such as astrocytes, microglia, and T cells. Research demonstrated that the MIP-1α/C-C chemokine receptor type 5 (CCR5) signaling pathway is responsible for stimulated glial cell aggregation, inflammatory reactions, and synaptic/cognitive dysregulation [76].
Vascular inflammation has been implicated as a progenitor of AD in the form of rheumatoid arthritis (RH), atherosclerosis, and cardiovascular disease (CVD). Vascular inflammation may be instrumental in elevating a myriad of proinflammatory mediators acting via cerebral microvessels such as TNF-α and IL-6 [77].
4.1. Oxidative Stress
Oxidative stress is a condition that is elevated in the brain with aging, produced by an imbalance in the redox state, involving the generation of excess ROS or the dysfunction of the antioxidant system. Due to the brain's excessive metabolic rate and decreased capacity for cellular regeneration, it is highly susceptible to ROS [78].
The brain also contains many phospholipids, which are rich in polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA) and arachidonic acid (AA). Research has shown that as free radical production rises, the PUFA content in the brain gradually decreases [79]. The lipid hydroperoxides are partially unstable and can automatically degrade into various products, such as malondialdehyde (MDA), 4-Hydroxynonenal (4-HNE), ketones, epoxides, and hydrocarbons in the presence of iron. In the AD brain, there is an elevated level of protein carbonyl.
Reactions of various ROS and reactive nitrogen species (RNS) with tyrosine lead to the production of 3-nitrotyrosine and tyrosine [79]. DNA oxidation can result in creating 8-Oxo-20 -deoxyguanosine (8-OHdG), which is highly expressed in the mitochondrial DNA of AD patients [79].
In all variations of ROS generation, molecular oxygen must be triggered, and the cellular system has evolved many metalloenzymes that facilitate ROS generation upon the interaction of redox metals with O2 utilizing various catalytic pathways [80].
The mitochondrial electron transport chain expends almost 98% of molecular oxygen at the cytochrome oxidase complex, and the remaining oxygen is reduced to hydrogen peroxide and superoxide radicals. During normal metabolism various functions of the oxygen radical superoxide anion −(O2 −•) the non-radical oxidant hydrogen peroxide (H2O2), and hypochlorous acid (HOCl or HClO) are created.
When the production of (O2 −) and (H2O2) becomes unrestrained, they can result in tissue damage that often involves the generation of the highly reactive hydroxyl radical (OH·) and other oxidant molecules in the presence of catalytic iron or copper ions [81]. The brain has abundant peroxidation-susceptible lipid cells and is an organ with a high indulgence for oxygen.
Moreover, the cerebrospinal fluid cannot bind expelled iron ions. Consequently, oxidative stress in nervous tissue may seriously damage the brain via several interconnected mechanisms, such as increased intracellular free Ca2+, the release of excitatory amino acids, and neurotoxicity [82].
Other progenitors of oxidative stress are RNS, NO, and peroxynitrite (ONOO−), which can be highly reactive with proteins, lipids, nucleic acid, and other molecules resulting in modifying the structure and functionalities and having detrimental effects on the brain.
Cells with an accumulation of oxidized products, i.e., aldehydes, protein carbonyls, and base adducts from DNA oxidation, can be seriously transformed. The large ROS formation elevated by the electron transport system within the mitochondria under stressful situations and aging comprises a risk for AD development [81].
NO not only contributes to oxidative stress but also functions in inflammation [83]. NO is an inflammatory mediator in various joint, gut, and lung diseases, i.e., rheumatoid arthritis [84].
NO association with the immune system and glial cells has garnered interest in mediating neurodegenerative diseases, such as AD and PD. Recent research has displayed NO's role in vascular dementia [85], in which similar inflammatory molecular mechanisms can be used in examining AD pathology.
4.2. Nitric Oxide
NO is a multifaceted mediator molecule that is expressed highly in the neurons [86,87]. The enzyme nitric oxide synthase (NOS) was isolated in 1990 in the rat brain (neuronal nNOS or NOS-1), as well as in macrophages (inducible iNOS or NOS-2) and endothelial cells (eNOS or N0S-3) [88].
The enzymatic reactions of iNOS are regulated transcriptionally by cytokines, whereas post-translational modifications via Ca2+/calmodulin control the activity of eNOS or nNOS [88]. Normally NO is steadily expelled in small increments and functions in vasodilation. Many different immune system cells (leukocytes, mast cells, platelets, and macrophages) produce and respond to NO [83,86].
NO halts platelet and leukocyte binding to the endothelium, which diminishes pro-inflammatory processes [86]. Aging and inflammation increase the generation of the ROS/RNS superoxide anion (O2 −•) that can react with NO to form peroxynitrite (ONOO-), which interferes with mitochondrial respiration and causes NO dyshomeostasis leading to mitochondrial dysfunction and neuronal death [88,89].
It has been shown that aging causes decreased eNOS-generated NO production, leading to increased cardiovascular risks, which can involve reducing the antioxidant activity, superoxide overproduction, and modifications of NOS enzyme/expression activity.
AD may be correlated with vascular degeneration in the central nervous acting via NO signaling dysregulation. Evidence shows that NO-mediated neurotoxicity in AD is caused by microglial cell stimulation, promoting INOS-regulated NO discharge [89]. Furthermore, pro-inflammatory cytokine TNF-α induces NO assembly. Immunoreactive components such as macrophages can produce superoxide through NADPH oxidase [87].
Microglia, glia, and neurons release high amounts of glutamate [89]. NO can halt respiration and cause glutamate release from synaptosomes and neurons, hindering mitochondrial respiration and reversing glutamate uptake or initiating vascular exocytosis [89]. NO has been shown to cause neuronal death via energy depletion-induced necrosis, oxidative phosphorylation, or excitotoxicity [83].
The mechanisms postulated to be involved, according to the paper by Brown and Bal Price [87], are as follows: (1) stimulation of poly ADP ribose polymerase (PARP) followed by nicotinamide adenosine diphosphate (NAD+ ) and ATP reduction, (2) promotion of apoptosis by weakly understood reactions, (3) glutamate release, and (4) halting of mitochondrial respiration.
Research has shown that cerebral blood flow diminishes with aging, promoting endothelial cell dysfunction regarding depressed NO discharge [87]. NF-κB is postulated to be involved due to its inflammatory regulatory properties; eNOS suppresses its activation via proinflammatory cytokines [87].
Microvascolopathy may arise due to the reduced NO release and NF-κB stimulation [87]. NO at reduced concentrations suppresses cytochrome oxidase in contention with oxygen and may serve as a mediator of cellular energy metabolism [88].
4.3. Autophagy
Autophagy is an evolutionarily preserved mechanism to sustain neuronal homeostasis during cellular development and maturation. It is maintained by lysosomal action, which controls nutrient recycling in starvation, neurotransmitter release, synaptic restructuring, and pruning during the growth of axons and dendrites [90].
To date, there are three major types of autophagy in mammals: (1) Macroautophagy, which refers to the isolation of cytoplasmic materials into double or multi-membrane vesicles called autophagosomes.
The process involves developed autophagosomal transport using microtubules in which cellular byproducts are delivered to degradative compartments; meanwhile, during this operation, lysosomes create autolysosomes. (2) Microautophagy involves the distinct engulfment of the cytosolic substance by invagination of the lysosomal membrane. (3) Chaperone-mediated autophagy (CMA), which consists of proteins having a pentapeptide pattern (KFERQ-like sequence) that are identified by the cytosolic chaperone heat shock cognate protein of 70 kDa (hsc70) and its co-chaperones distribute them to the cell surface of lysosomes [91].
Autophagy plays a pivotal role in cell survival by safeguarding stressful situations, i.e., ER and metabolic stress. Selective autophagy allows better organelle regulation, limiting the dysfunctional compartment, and pathogen disposal by uniting the ubiquitin-proteasome system (UPS) and autophagic apparatus. As efficient as this process may be, conditions caused by overabundance and destabilization can lead to cell death [92–94].
Aging and inflammation act as precursors to autophagic dysregulation and bolster cell death by exacerbating the cellular burden of misfolded and damaged cellular deposits and diminishing cellular degradative capacity cells and other modifications of intracellular proteolytic systems [95]. It has been demonstrated that autophagy modulates critical elements of the immune system, namely, macrophages, lymphocytes, and neutrophils [96].
Autophagic proteins (Beclin1 or ATG16L1) can mediate proinflammatory cytokine production in macrophages and other inflammatory regulators. It can also, in turn, control cytokine production itself, acting through Il-1β. Countless research in various mammalian organisms (rodents and humans) has shown that aging contributes to oxidative stress, DNA damage, and telomere shortening resulting in impaired autophagy, and promoting AD genesis [97,98].
Recent research has shown that in AD, mitophagy (a form of selective autophagy that involves the mitochondria) dysregulation leads to the aggregation of mitochondrial debris and destabilization of mitochondrial integrity leading to cell death [93,97].
The thoroughly researched process of the phosphatase and tensin homolog (PTEN)-induced the kinase 1 (PINK1)-Parkin pathway depicts the decline of the mitochondrial membrane potential, which increases PINK1 on the outer membrane of mitochondria (OMM) to enlist and switch on Parkin, a ubiquitin ligase, via phosphorylation of ubiquitin.
Parkin ubiquitinates numerous OMM proteins, which stimulate the UPS to degenerate these ubiquitinated OMM proteins, resulting in the mobilization of the autophagy machinery to instigate the engulfment of impaired mitochondria by phagophore or secluded membranes and thus create mitophagosomes reserved for removal via the lysosomal system [99].
Evidence of oxidative stress within the AD brain includes (1) lipid peroxidation, in which lipid byproducts, i.e., 4-hydroxy-2,3-nonenal (HNE); (2) protein oxidation in the form of 3-nitrotyrosine and protein carbonyls were observed in the hippocampus of AD patients; and 3) DNA/RNA damage leads to disrupted DNA repair mechanisms and elevated DNA mutations exhibited within the hippocampus and cerebral cortex [100].
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