Emerging role of antioxidants in Alzheimer's disease: Insight into physiological, pathological mechanisms and management

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory loss, cognitive decline, impairment in activities of daily living, and loss of independent function. Cognitive decline and brain shrinkage, particularly hippocampal atrophy, are associated with the accumulation of tau proteins. They cause inflammation, amyloid plaque deposition, neuronal loss, temporofrontal cortex atrophy, aberrant protein fragment clusters, and twisted fiber bundles. Given the significant role of oxidative processes in neurodegeneration, it is logical to consider the potential of antioxidants in the treatment of AD. Several antioxidants, including glutathione, astaxanthin, ascorbyl palmitate, catalase, and molecular hydrogen, play important roles in AD. Antioxidants interact with free radicals to neutralize them. Several studies have suggested that oxidative stress or damage is involved in the development of AD via different mechanisms and pathways. Thus, new approaches are needed to reduce the extent of oxidative damage that may be therapeutically effective against AD. Although certain antioxidants have exhibited notable benefits in animal models, their efficacy in human clinical trials has been limited, casting doubt regarding the efficacy of antioxidant treatments for AD. Therefore, a more focused and precise strategy that incorporates antioxidants is essential for slowing or stopping AD progression. The integrated role of antioxidants in reducing inflammation must be considered, because the link between inflammation and AD is undeniable. Therefore, the present study aimed to elucidate the role of antioxidants in AD, with the goal of aiding researchers in developing effective and potentially enhanced antioxidant-based therapeutic strategies.

Abbreviations

AD

Alzheimer's disease

Aβ

Amyloid-beta

ROS

Reactive oxygen species

RNS

Reactive nitrogen species

SP

Senile plaques

DNA

Deoxyribonucleic acid

Cu

Copper

Fe

Iron

H₂O₂

Hydrogen peroxide

GSH

Glutathione

GSSG

Glutathione disulfide

ASX

Astaxanthin

PCD

Programmed cell death

SOD

Superoxide dismutase

NADPH

Nicotinamide adenine dinucleotide phosphate

XO

Xanthine oxidase

1. Introduction

Alzheimer's disease (AD) is a progressive neurodegenerative disease of the brain that is characterized by memory loss, increased cognitive decline, neuropsychiatric symptoms, behavioral problems, impairment of daily living activities, and loss of independent function [1]. It primarily affects individuals over 65 years of age and influences various cognitive functions, including language, memory, understanding, attention, judgment, and reasoning [2]. Notably, more than 60% of the 55 million people with dementia worldwide reside in low- and middle-income countries. Given that the proportion of older adults in the population is growing in almost every country, it is predicted that this number will increase to 78 million by 2030 and 139 million by 2050 [3]. On a broad scale, AD pathology may be described as a continuous loss of the brain tissue. Memory loss, particularly in short-term recall, represents an initial symptom of AD. The hippocampus is one of the brain regions responsible for memory. Preclinical AD manifests in the entorhinal cortex, which links the cerebral cortex to the hippocampus [4].

Various brain regions, including the hippocampus, amygdala, entorhinal cortex, and the cortical association regions within the frontal, temporal, and parietal cortices, along with subcortical nuclei, such as the dorsal serotonergic raphe, noradrenergic locus coeruleus, and basal cholinergic nucleus, are susceptible to neuronal loss and pathological changes. The accumulation of tangles typically begins in the transentorhinal cortex, followed by the entorhinal cortex, CA1 region of the hippocampus, and cortical association regions, where the frontal, parietal, and temporal lobes are the most severely affected. The severity of dementia is closely associated with the quantity of amyloid plaques and the degree and location of tangles [5].

Cognitive decline and brain atrophy, particularly in the hippocampus, are associated with the accumulation of tau proteins. AD is characterized by inflammation, amyloid plaque deposition, neuronal loss, atrophy of the temporofrontal cortex, aberrant protein fragment clusters, and twisted fiber bundles. As a result, the number of monocytes and macrophages in the cerebral cortex increases, and parenchymal microglia are activated [6,7](Fig. 1).

Fig. 1.

Neurobiological mechanisms involved in the pathogenesis of AD causes by cholinergic dysbalance, oxidative stress and accumulation of metal ions. A schematic diagram illustrating neurobiological mechanisms that leads to the onset and development of AD [7].

Antioxidants are widely used to combat oxidative stress, and those derived from natural sources, often incorporated into dietary regimes, may play an important role in delaying the onset and reducing the progression of AD. However, this approach has not been explored extensively. Moreover, combining antioxidants with a nutrient-rich diet may offer greater efficacy in addressing the pathogenesis of AD.

Cellular antioxidant systems are not solely reliant on endogenous or exogenous small molecules acting as scavengers, but also involve antioxidant enzymes that use specific substrates to reduce oxidants. Therefore, the primary therapeutic prospects are to reduce the production of oxidants that directly damage macromolecules, prevent oxidant-induced downstream signaling that causes inflammation or cell death, and increase the levels of antioxidant enzymes and their substrates. This article explores the relationship between redox signaling, oxidative stress, and AD, providing an overview of the mechanisms through which oxidative stress contributes to pathology in AD [8]. We discuss the current understanding of the factors limiting the efficiency of antioxidant defenses and explore potential treatment approaches to modulate these factors. An effective therapeutic intervention strategy can be established with an enhanced understanding of how oxidants function and the limitations and potential of antioxidant therapy. Thus, in light of these considerations, we aim to elucidate the fundamentals of AD and antioxidants (endogenous and exogenous), including the vitality of antioxidants in AD. Furthermore, we hypothesize that these antioxidants may hold to potential to facilitate the development of effective and potentially enhanced antioxidant-based therapeutic strategies for AD, including insights from clinical trials in the field.

2. Hypothesis in Alzheimer's disease

Given the significant role of oxidative processes in neurodegeneration, it is reasonable to hypothesize that antioxidants may offer a potential cure for AD. Antioxidants interact with and neutralize free radicals and can mitigate lipid peroxidation triggered by these free radicals. However, in addition to lipid peroxidation, free radicals may harm DNA, proteins, and nearly any other biomolecule. Numerous studies have demonstrated that oxidative stress is a precursor to AD and that antioxidants mitigate its harmful effects [9] (Fig. 2). Furthermore, according to theories, changes in the levels and activity of antioxidant enzymes in the brain may enhance oxidative damage in AD. We have focused on investigating some of the most potent antioxidants that play a crucial role in neuroprotection.

Fig. 2.

Antioxidant enzyme schematic. There are three major types of primary intracellular antioxidant enzymes in mammalian cells: superoxide dismutase, catalase and glutathione. The SOD converts O2•− into H2O2, whereas the catalases and glutathione convert H2O2 into water [[6], [7], [8], [9]].

2.1. Hyperphosphorylated tau protein and amyloid-beta

Senile plaques (SPs), resulting from the accumulation of amyloid beta (Aβ), are one of the key pathogenic characteristics of AD. Typically, Aβ is a soluble short peptide that is cleaved from the amyloid precursor protein (APP) through the actions of α-secretase, β-secretase, and γ-secretase. Depending on the degree of oligomerization, an imbalance between the generation and clearance of Aβ leads to the formation of several toxic oligomeric forms, including protofibrils, fibrils, and plaques [10].

Following its initial formation in the temporal and orbitofrontal cortices, amyloid deposition subsequently occurs in several key regions, including the frontal, parietal, precuneus, anterior, and posterior cingulate cortices [11]. Um et al. (2017) [12] reported the case of a 37-year-old man who visited an outpatient clinic due to gradual cognitive decline which had started three years ago. Unlike the typical uptake patterns observed in patients with late-onset AD, where the stratum is generally involved in the later course of the disease, a dominant striatal uptake pattern in was observed in this patient upon using ¹⁸F-Florbetaben amyloid imaging. Previous research on individuals with autosomal early-onset AD has consistently shown substantial striatal amyloid accumulation [[13], [14], [15]]. In this case, the patient was diagnosed with early-onset AD, which was confirmed by Aβ imaging.

2.2. Oxidative stress

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are formed as byproducts of many normal and pathological processes in humans [16] (Fig. 3). Oxidative stress has been implicated in the progression of AD and other neurodegenerative diseases [17]. The hallmarks of AD include the extracellular formation of SPs and intracellular accumulation of neurofibrillary tangles, which are associated with the formation of the Aβ peptide along with metal ions, such as copper (Cu), iron (Fe), or zinc (Zn) [[18], [19], [20]]. Nunomura et al., investigated the levels of 8-hydroxyguanosine (8OHG), an oxidized nucleoside originating from RNA, and nitrotyrosine, a protein modification, to address the temporal aspect of oxidative stress in AD patients with varying disease durations. Significant 8OHG immunoreactivity was observed in the temporal neocortex, entorhinal cortex, subiculum, and neuronal cytoplasm of the patients. Their findings suggest that oxidative damage to neuronal RNA and proteins represents an early event in the pathophysiology of AD, consistent with previous studies in Down syndrome, where neuronal oxidative stress preceding Aβ deposition was observed [21]. These oxidative species have a dual role, i.e., they have beneficial effects with respect to signaling pathways as well as toxic effects that may cause harm to cellular structures.

Fig. 3.

Diagram representing the effect of oxidative stress in neurodegenerative disorders. The imbalance in the level of antioxidants and ROS/RNS leads to an oxidative stress that damage the lipids, proteins, DNA and mitochondria. Mitochondrial dysfunction and accumulation of activated microglia and astrocytes release pro-inflammatory cytokines and chemokines, promoting cellular apoptosis and neuronal cell death [16].

2.3. Lipid oxidation

Lipid oxidation is a well-known phenomenon that occurs when lipids (fats) are exposed to oxidative stress, leading to the formation of ROS and other free radicals [22]. This process can result in damage to cell membranes and contribute to various diseases, including AD. In AD, lipid peroxidation is a significant contributor to the development and progression of the disease [23]. One of the features of AD is the accumulation of Aβ peptides in the brain, which can trigger oxidative stress and lipid peroxidation. One possible mechanism underlying lipid oxidation in AD is the formation of Aβ plaques. These plaques stimulate lipid peroxidation, leading to the production of oxidized lipids. Another potential mechanism of lipid oxidation in AD involves the activation of inflammatory pathways [24]. ROS, altered lipids, lipid peroxides, antioxidant enzymes, SPs, and NFTs are closely associated with AD. Markesbery et al. demonstrated that lipid peroxidation plays a significant role in decreasing the levels of membrane phospholipids in AD [25]. Studies have shown that the levels of lipid peroxidation markers are elevated in the brains of patients with AD, underscoring the significance of oxidative damage to lipids in the disease. In addition to damaging cell membranes, lipid peroxidation products can cause inflammation and oxidative stress, leading to a vicious cycle of damage and dysfunction in the brain [26]. This ultimately leads to neuronal death and cognitive decline associated with AD. Numerous studies have investigated the use of antioxidants to prevent or slow down AD progression by reducing oxidative stress and lipid peroxidation [27]. Overall, lipid oxidation, subsequent cell membrane damage, and inflammation are important factors in the AD pathogenesis. Further research is required to gain a better understanding of the underlying mechanisms and to identify new therapeutic targets for preventing and treating this devastating disease.

2.4. DNA oxidation

Oxidative stress has been implicated in the pathogenesis of AD, with one of its manifestations being DNA oxidation, which refers to the process by which ROS damage DNA molecules, forming modified bases, strand breaks, and other types of DNA damage [28]. Studies have demonstrated an increase in oxidative DNA damage in the brains of individuals with AD. DNA oxidation in AD is caused by various factors, including mitochondrial dysfunction, inflammation, and accumulation of metals such as Fe and Cu in the brain [29]. Mitochondrial dysfunction can lead to increased ROS production, causing oxidative DNA damage. Inflammation, which is common in AD, can generate ROS and promote the production of inflammatory mediators that can further damage DNA. Fe and Cu can also catalyze ROS production through the Fenton reaction, leading to oxidative DNA damage [30]. DNA damage caused by oxidation can result in mutations and chromosomal abnormalities that contribute to the pathogenesis of AD. For example, oxidative damage to DNA can lead to the accumulation of Aβ plaques and tau protein tangles, which are key pathological features of AD. Additionally, DNA damage can impair the function of molecules involved in processes such as neuronal signaling and DNA repair, further exacerbating the disease [31]. A study has shown that levels of 8-oxo-2′-deoxyguanosine (8-oxo-dG), a marker of DNA oxidation, are significantly higher in the brains of individuals with AD than in healthy individuals. Other studies have reported increased levels of DNA damage and impaired DNA repair mechanisms in the brains of patients with AD. It is believed that DNA oxidation can contribute to the pathogenesis of AD by promoting neuronal death, impairing mitochondrial function, and promoting inflammation [32]. Oxidative damage to DNA can also lead to the accumulation of Aβ plaques and tau protein tangles, which are hallmarks of AD. Evidence suggests that antioxidant therapy may be beneficial with respect to reducing DNA oxidation and slowing the progression of AD [33]. Antioxidants can scavenge ROS and prevent oxidative DNA damage, potentially mitigating the effects of oxidative stress in the brain. However, the effectiveness of antioxidant therapy in AD remains a topic of debate, as some studies have reported positive effects, whereas others have not. In summary, DNA oxidation is a key feature of oxidative stress associated with AD and can contribute to its development and progression through a variety of mechanisms [34]. Further research is needed to better understand the role of DNA oxidation in AD and identify effective therapeutic strategies to mitigate its effects.

2.5. Protein oxidation

Protein oxidation is a process in which proteins are chemically modified by ROS, such as superoxide radicals and hydrogen peroxide (H₂O₂), leading to the formation of carbonyl groups on amino acid residues. This modification can impair protein structure and function, leading to the aggregation and formation of toxic species [35]. Tyrosine reacts with ROS and RNS, converting them into 3-nitrotyrosine and dityrosine. Mental status evaluation has shown an inverse relationship with the concentration of the 3-nitrotyrosine residue in the cerebrospinal fluid [13,14]. A study revealed significantly higher levels of total protein nitration in the inferior parietal lobule and hippocampus of patients with mild cognitive impairment compared to healthy controls, indicating that protein nitration begins early in AD pathogenesis.

One specific example of protein oxidation in AD is the tau protein. Tau is a microtubule-associated protein that stabilizes the neuronal cytoskeleton [36]. In AD, tau is hyperphosphorylated, a phenomenon that leads to its aggregation into neurofibrillary tangles. In addition to hyperphosphorylation, tau can be modified by ROS and RNS, which can cause structural and functional changes [37]. There is also evidence that the oxidative modification of proteins involved in synaptic function, such as synaptophysin and PSD-95, can contribute to synaptic dysfunction in AD. Overall, protein oxidation is believed to play a significant role in the pathogenesis of AD, and strategies aimed at reducing oxidative stress and protein oxidation hold promise for the development of therapeutic interventions for the disease [37].

2.6. Metal ions

Metal dyshomeostasis plays a role in the development and pathophysiology of various diseases, including cancer and neurodegenerative disorders. Several metals have been investigated in clinical studies. The ionosphere and metal chelators are well-known modulators of transition metal homeostasis. Other metal-binding drugs can also target the homeostasis of transition metals. Current findings have shed light on the altered balance of redox transition metals, specifically Cu, Fe, and other trace metals, within the brain in the context of AD [38]. Evidence suggests that the excessive accumulation of certain metals, particularly Cu and Fe, in the brain can cause oxidative damage to neurons and contribute to AD development [39]. Research on the relationship between metal ions and AD is ongoing and much remains to be learned about the exact mechanisms by which metal ions may contribute to the development and progression of the disease. Recent studies have suggested that the accumulation of Cu in the brain may promote the formation of toxic Aβ oligomers, which are believed to play a key role in the development of AD [39]. Other studies have focused on the potential therapeutic benefits of targeting metal ions for the treatment of AD.

Although research has indicated that metal ions contribute to the onset of AD, some studies have reported conflicting results. Cu ions attach to tau proteins and encourage NFT production, but the precise effects of Cu and tau on AD are unclear and require further research to unravel this relationship, despite the significance of tau and Aβ as important pathogenic alterations in AD [40]. Cu has been shown to increase the production of pro-inflammatory molecules, such interleukin (IL)-1β, tumor necrosis factor-alpha (TNF-α), and IL-6, while decreasing the expression of LRP1, indicating that the inflammation it induces is one of the factors influencing the initiation of AD [41]. Notably, the reduction of TNF-α or nitric oxide (NO) levels alone does not prevent neuronal death. However, the combined suppression of TNF-α and NO may yield this outcome. Hence, it is hypothesized that the combination of TNF-α and NO could have detrimental effects on neurons [41]. Research on metal chelators must consider strategies to modulate this equilibrium.

3. Antioxidants in Alzheimer's disease

Antioxidants play a crucial role in AD as they react with and neutralize free radicals. Antioxidants decrease inflammation, modify signaling pathways, protect against oxidative stress, and maintain the intracellular oxidative balance. Table 1 lists the antioxidants, their effects, and biological actions. Antioxidants effectively reduce the rate of oxidative stress even at low doses. They can be categorized into two groups based on their mechanism of action, i.e., primary and secondary. The former is responsible for eliminating free radicals and inhibiting chain reactions that culminate in oxidative stress. They oxidize and convert hydroperoxides into stable forms. Secondary antioxidants enhance antioxidant renewal, deactivate metal ions, and reduce singlet oxygen. The body possesses a complex natural antioxidant system that protects it from pro-oxidants and prevents damage. Certain dietary sources also contribute to antioxidant systems. Therefore, antioxidant systems can be classified as either exogenous or endogenous. Exogenous antioxidants are obtained through diet, whereas endogenous antioxidants are produced within the body. Studies have indicated that antioxidant therapies have potential benefits in the treatment of neurodegenerative disorders [42]. Therefore, we focused predominantly on recent developments in commonly used antioxidant therapies for AD, providing insights into potential antioxidant-based therapeutic strategies.

Table 1.

List of antioxidants and nutraceuticals with their biological actions.

Antioxidant and nutraceuticals	Effect or biological action	References
Molecular hydrogen	A superb antioxidant that also lowers inflammation and modifies signaling pathways. Acting as their source, diffusions into mitochondria and the nucleus react with free radicals. The hydroxyl radical is diminished. Reduces the buildup of ROS brought on by beta amyloid. Prolonged lifetime, memory impairment, and suppressed learning. Enhanced word recall ratings. Elevates levels of glutathione and superoxide dismutase.	[[30], [31], [32], [33]]
Glutathione	Maintains cells' thiol redox status stable, protect against oxidative stress, and detoxes electrophiles and reactive metals. Scavenges the byproducts of lipid peroxidation. beneficial for older people to retain excellent health.	[33,34]
Astaxanthin	Neuroprotective characteristics of the strongest carotenoid reduces apoptosis, inflammation, and oxidative stress defends against beta amyloid oligomer's neurotoxic effects diminution of memory impairment.	[35,43]
Ascorbyl palmitate	Maintains vitamin C activity without ascorbic acid's adverse affects. It acts as powerful hydroxyl radical scavenger. Capable of overcoming the blood-brain barrier. Rebuilds vitamin E	[44,36]
Catalase	The intracellular oxidative balance is maintained primarily by catalase. Hydrogen peroxide (H2O2) contains heme and is converted to water and oxygen by catalase, a tetrameric antioxidant enzyme that resides primarily in peroxisomes.	[ [[37], [38], [39], [40]]
Superoxide dismutases	A class of metallo-coenzymes are called superoxide dismutases. SODs are the first line of defence against damage caused by reactive oxygen species (ROS). These proteins reduce the quantity of superoxide anion free radical (O2−), which when present in excessive amounts harms cells, by catalysing its dismutation into molecular oxygen and hydrogen peroxide (H2O2).	[41,42]

3.1. Role of molecular hydrogen

Molecular hydrogen exhibits antioxidant effects by directly neutralizing hydroxyl radicals and decreasing peroxynitrite levels. Additionally, it activates Nrf2 and HO⁻¹, which control a variety of antioxidant enzymes and proteasomes. Furthermore, molecular hydrogen plays a role in histone modification, telomere preservation, and proteostasis through its antioxidant effect, thereby preserving genomic integrity and slowing cellular ageing [45]. It is an exceptional antioxidant that provides cytoprotection by reducing inflammation and altering various signaling pathways.

Although molecular hydrogen was initially considered biologically inert, research has demonstrated its ability to protect cultured cells and the brain against excess oxidative stress. Consequently, molecular hydrogen exhibits significant potential for preventive and therapeutic applications in various medical conditions. As a molecular mechanism through which molecular hydrogen exerts its multifunctional effects, it may indirectly regulate the expression of various genes via transcription factors. Several studies have reported that the consumption of hydrogen-enriched water can prevent cognitive decline, maintain neural cell proliferation, and inhibit oxidative stress in a mouse model of dementia subjected to chronic restraint stress [46]. These studies observed that hydrogen-enriched water effectively suppressed the increase in the levels of malondialdehyde and 4-hydroxy-2-nonenal, recognized as oxidative stress markers whose content is elevated in response to chronic restraint stress. Simultaneously, hydrogen-enriched water restored the counts of proliferating cells in the dentate gyrus after restraint stress.

3.2. Role of glutathione

Glutathione (GSH) is an endogenous enzyme-catalyzed antioxidant crucial for detoxifying ROS and regulating the intracellular redox balance [32,33]. GSH can potentially be leveraged in the development of effective treatments for AD that would function by targeting essential molecular elements involved in AD pathogenesis [[47], [48], [49]]. Several in vitro and in vivo studies have shown that GSH protects neurons against oxidative stress [35,43]. GSH deficiency in the brain exacerbates oxidative stress-related brain damage [44,36]. In neuronal cells, GSH counteracts the damaging effects of ROS, and GSH deficiency leads to increased apoptotic signaling and subsequent neuronal death [[50], [51], [52], [53], [54]]. A study has shown that the GSH/glutathione disulfide (GSSG) ratio in the brain of an AD transgenic mouse model decreased as AD progressed. Notably, this decrease occurred shortly before amyloid plaque formation, followed by a continuous increase in GSSG levels and a corresponding decrease in the GSH/GSSG ratio [[55], [56]]. Furthermore, in the hippocampus and inferior parietal lobe of patients with AD, mRNA levels of GSH reductase and GSH peroxidase enzymes, which are involved in GSH antioxidant activity against free radicals, are elevated [39,40].

Several studies have demonstrated that Aβ oligomers stimulate the production of ROS; however, this area of research remains in its early stages. Oxidative alterations in several cellular proteins triggered by ROS production can impair their function. Recent studies suggest that the oxidative modification of proteins involved in Aβ peptide formation may increase Aβ production. GSH is a potent antioxidant that reduces Aβ-induced oxidative damage. Preliminary in vitro data indicate that GSH may directly attenuate AD pathogenesis by reducing Aβ accumulation [[57], [58]] (Fig. 4).

Fig. 4.

Diagram showing the intricate relationship between oxidative stress, amyloid-β peptides, and the probable function of glutathione in controlling the pathogenesis of AD [57].

3.3. Role of astaxanthin

Astaxanthin (AST) is a red xanthophyll carotenoid found in freshwater environments that is produced by marine microorganisms, such as bacteria, yeasts, and fungi, with the richest source being the microalga Haematococcus pluvialis [1,59,60]. AST is consumed by fish such as salmon and trout, thereby imparting a dark red-orange pigment to their flesh [61,62]. It possesses significant antioxidant and anti-inflammatory properties and plays a role in the functioning of cell membranes and circulating lipoproteins [40,41,63]. In combination with canthaxanthin, AST is used as a feed to color the flesh of salmon, trout, and prawns [64]. Globally, AST from various sources is increasingly being used as food and nutritional supplement. Pharmaceutical applications of AST products encompass various dosage forms, including tablets, capsules, soft gels, lotions, oils, biomass, and granulated powders [65]. AST has advantageous attributes that make it a valuable antioxidant and food colorant for enhancing the nutritional content and sensory quality of foods. It has gained attention for its potential pharmacological properties, including its anti-inflammatory, antioxidant, neuroprotective, and skin-protective effects. Previous research has shown that AST exhibits excellent therapeutic potential against several conditions, including neuroinflammation [66], ophthalmic disorders [67], and cardiovascular, aging-related, neurodegenerative, respiratory, and liver diseases, owing to its high biosafety and bioavailability.

AST neutralizes ROS and RNS, thereby reducing oxidative stress [68]. Mitochondrial dysfunction resulting from oxidative stress is recognized as a key contributor to aging, with mitochondrial ROS having the greatest effect on aging. ROS associated with ageing can be generated endogenously or exogenously, contributing to the detrimental effects of aging, such as cognitive decline and decreased brain mobility [69]. AST demonstrates potent anti-inflammatory effects by inhibiting the expression of inflammatory mediators, such as TNF-α, PGE2, and IL-1, and preventing the production of NO and the NF-κB-dependent signaling pathway. Similar anti-inflammatory effects of AST have been reported in studies that employed distinct experimental designs. Specifically, AST (50 μM) reduced the release of inflammatory mediators in activated microglial cells (BV-2 cell line) by modulating factors involved in the NF-κB cascade (such as p-IKKα, p-NF-κB, p-IκBα, p65, MAPK, and IL-6) [70]. The ability of AST to suppress microglial activation and the subsequent release of proinflammatory cytokines validates its potential as an adjuvant therapy for AD. This effect has a positive impact on neuronal integrity, particularly in older adults who exhibit increased brain inflammation [70,71].

3.4. Role of ascorbyl palmitate

Ascorbic acid (vitamin C) is present in the form of ascorbyl palmitate, a highly bioavailable fat-soluble compound that has the same benefits as its water-soluble counterpart. It is a potent antioxidant, capable of scavenging free radicals and protecting lipids from oxidation [72]. Ascorbyl palmitate can successfully cross the blood-brain barrier and plays a significant role in the treatment of AD. As ascorbyl palmitate resides in the cell membrane, it can accelerate the production of vitamin E. However, the protective role of vitamin C remains a topic of debate, as it is unclear whether it acts independently or synergistically to treat AD [73]. Providing vitamin C in its lipophilic rather than hydrophilic form, will better satisfy the tissue demands. Ascorbyl palmitate is amphipathic in nature and is concentrated in the phospholipid membranes of biological systems, with the ascorbate head embedded in the inner membrane and the fatty acid intercalated into the outer layer of the lipid bilayers [74].

Furthermore, ascorbyl palmitate may continually replenish vitamin E radicals, unlike ascorbic acid, which only regenerates vitamin E radicals at the interface of the water-soluble and lipid components. Several studies have attempted to determine whether vitamin C supplementation, either alone or in conjunction with other supplements such as vitamin E, reduces the risk of AD. While some studies have suggested that vitamin C supplementation reduces the risk of AD, others have produced inconclusive results, necessitating further long-term investigations. In a randomized study involving various antioxidants and their effects on inclusion bodies in the brain of ApoE-deficient mice, the group receiving ascorbyl palmitate had the lowest number of inclusion bodies [75]. This suggests that ascorbyl palmitate crosses the blood-brain barrier and may be an antioxidant that should be considered in future AD research.

3.5. Role of catalase

Catalase (CAT, 1.11.1.6) is an enzyme present in all living organisms, spanning from unicellular prokaryotes to multicellular eukaryotes. During photosynthesis and respiration in aerobic organisms, damage can occur due to the production of ROS, superoxide anions (O₂⁻), hydroxyl radicals (OH), H₂O₂, and singlet oxygen (O₂). Elevated ROS production can induce various effects, including lipid peroxidation, protein oxidation, nucleic acid damage, enzyme inhibition, programmed cell death (PCD) pathway activation, and eventual cell death, placing cells under oxidative stress [76]. CAT exists in many isoforms (CAT1, CAT2, CAT3) encoded by numerous genes (CAT1, CAT2, CAT3), which are expressed in organelle-, temporal-, and stress-specific patterns. Phylogenetic analysis of CAT isozymes has revealed distinct evolutionary processes, including horizontal gene transfer, paralog formation, and gene fusion. Although significant efforts have been made to understand CAT in prokaryotes and mammals, little is known about its adaptability in plants [76].

CAT plays a crucial role in managing oxidative stress-related disorders by decomposing H₂O₂ into harmless water and oxygen [59]. Acting as a key regulator, CAT exerts a significant impact on H₂O₂ metabolism [[63], [64], [65], [66]], thereby influencing H₂O₂ levels which are essential for signaling [62]. The interaction between CAT and Aβ may significantly contribute to increased H₂O₂ levels within the cells, thereby linking Aβ accumulation to the development of oxidative stress conditions in AD [77]. According to a recent study, Aβ directly interacts with CAT, inhibiting its catalytic function and subsequently leading to oxidative stress and Aβ-stimulated oxidative damage in cells.

3.6. Role of superoxide dismutases

Superoxide dismutases (SODs are a group of metalloenzymes that are widely distributed among aerobic organisms, aerotolerant anaerobes, and obligate anaerobes [78]. These enzymes contain Zn and Cu (CU-Zn-SOD), manganese (Mn) or Fe [79]. Functioning in the presence of oxygen, SODs catalyze the conversion of superoxide into oxygen and H₂O₂. Superoxide (O₂⁻) is an anionic oxygen radical generated through the univalent reduction of oxygen. Superoxide anions are produced as a byproduct of mitochondrial respiration by enzymes such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, xanthine oxidase (XO), and cyclooxygenase. SODs are essential for defense against oxygen toxicity and are mediated by partially reduced oxygen intermediates. They catalyze the dismutation of superoxide anion free radicals (O²⁻), which damage cells when present in excess amounts, into molecular oxygen and H₂O₂. These enzymes possess anti-inflammatory properties and offer protection against precancerous cell alterations [[80], [81], [82]]. Additionally, SOD enzymes play pivotal roles in signaling pathways by regulating ROS activity and shielding cells from superoxide radical toxicity. Furthermore, intracellular SODs prevent superoxide damage to the Fe-S cluster-containing enzymes [71,72]. Studies have shown that SOD deficiency accelerates amyloid oligomerization and memory loss in rodent AD models. Overexpression of mitochondrial MnSOD can reduce Aβ synthesis and prevent neural apoptosis caused by Aβ. Furthermore, SOD deficiency has been associated with increased phosphorylation of tau in an AD mouse model [72].

4. Exogenous antioxidants and their formulations

Dietary antioxidants are essential for maintaining health because they inhibit the formation and prevent the damaging effects of ROS and RNS. As endogenous antioxidant mechanisms are insufficient to completely prevent such damage, diet-derived antioxidants are crucial for maintaining health. The exogenous dietary antioxidants that have been studied include vitamins C, E, and β-carotene.

Vitamin C is the most significant water-soluble antioxidant in extracellular fluids because it can neutralize ROS in the aqueous phase before lipid peroxidation. Vitamin E is a potent lipid-soluble antioxidant, particularly effective at breaking the chain reaction of lipid peroxidation within cell membranes, protecting fatty acids from lipid peroxidation. β-carotene and other carotenoids protect lipid-rich tissues from free radical damage, but less efficiently [83]. Besides conventional vitamins, there are several dietary antioxidants known as phytonutrients or phytochemicals [84]. Flavonoids are an important class of naturally occurring antioxidants, renowned for their contributions to human health. They can be found in leaves, flowers, fruits, apples, onions, seeds, nuts, grains, spices, olive oil, and various medicinal plants, as well as in drinks such as red wine, green tea, and beer, which contain a wide variety of phytochemicals [[85], [86], [87]]. The most powerful flavonoids can scavenge ROS and bind transition metal ions (such as Fe and Cu), thereby protecting organisms from oxidative damage [88,89].

Furthermore, quercetin offers various health benefits and serves as an effective regulator of the apoptotic cell death program, influencing various signaling molecules, including protein and lipid kinases [90]. Recent studies suggest that flavonoid consumption may enhance cognitive function and reduce the risk of neurodegenerative diseases. These benefits may be attributed to the promotion of synaptic plasticity and neurogenesis, inhibition of oxidative stress-related neuronal cell damage, and activation of key transcription factors that control the expression of inflammatory genes like NF-κB and AP-1 [91,92]. As the control of NF-κB and AP-1 transcription factors and MAPK pathways is sensitive to redox, the anti-inflammatory effects of flavonoids may positively affect their antioxidative properties. Notably, recent research indicates that several flavonoids, including quercetin, luteolin, and catechins, may exhibit superior antioxidative activity compared to vitamins C, E, and β-carotene [93]. As quercetin has greater antioxidative effect than vitamin C, it may be a more effective treatment for AD and other central nervous system diseases [94]. Continuous therapy with quercetin (20 and 40 mg/kg, p.o.) has been demonstrated to significantly ameliorate colchicine-induced cognitive impairment, reducing elevated lipid peroxidation, and restoring depleted reduced GSH levels, acetylcholinesterase activity, and nitrite activity [95]. In summary, the use of flavonoids as medicinal therapies offers great potential for the prevention and treatment of aging and neurodegenerative diseases [96].

5. Conclusion and perspective

AD is a neurodegenerative disease with a prolonged asymptomatic phase. Several studies have suggested that oxidative stress or damage is involved in the development of AD through different mechanisms and pathways. Thus, novel therapeutic approaches are needed to stop or reduce oxidative damage and potentially provide therapeutic benefits against AD. The incorporation of natural bioactive compounds into the diet is a common preventative strategy against AD, which can also complement established medications for patients with progressive AD. Combining antioxidants with several drugs may enhance their effectiveness. While several antioxidants have demonstrated beneficial effects in AD, others require further investigation.

Epidemiological investigations and human clinical trials have provided insights into the significance of antioxidants in AD. However, clinical studies exploring the use of antioxidants for AD prevention and treatment are still in their early stages. Determining whether antioxidants can effectively reduce the risk of AD or delay disease progression in patients requires extensive research. Future research should aim to elucidate the role of antioxidant consumption, offering deeper insights into how individuals can lead healthier lives free from the burden of neurodegenerative disorders. Ultimately, ongoing and future research endeavors have the potential to provide a clearer understanding of the impact of antioxidant consumption, thereby contributing to a healthier lifestyle that is free of neurodegeneration.

Author's contribution

Kamaljeet and Khadga Raj Aran summarized the literature and wrote the manuscript. Dr. Shamsher Singh and Dr. G.D. Gupta provided writing ideas and guided manuscript revision. All the authors have read and agreed to the published version of the manuscript.

Consent for publication

Not applicable.

Data availability statements

Data supporting the findings of this study will be provided upon reasonable request.

Ethics approval

Not applicable.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of competing interest

The author declares no conflict of interest.