1. Introduction

Selenium is a chalcogen element with unique chemical- activities [1-5]. It was discovered by Swedish chemist Jones Jacob Berzerius in 1818 and was initially considered as a toxic element for human beings and livestock for nearly 150 years. It can exist naturally in inorganic forms such as selenite and selenate, or in organic forms such as selenocysteine and selenomethionine. In middle twentieth century, selenium was found to be an essential trace element for health. It widely exists in natural products and can be found in seafood, peas, lentils, legumes, whole grains, organ meats, dairy products, and vegetables [6-9]. Meanwhile, it is also an indispensable element for the body [10, 11]. Selenium participates in biological processes such as biological oxidation, cell differentiation, protein synthesis, and gene transcription, and it exhibits strong antioxidant and immune functions, playing a crucial role in maintaining human health [12]. Selenium deficiency is related to cognitive impairment. In rural areas with low soil selenium content in China, a decrease in physical selenium levels is associated with a decline in cognitive ability [13, 14]. Not only does selenium exist in abundant forms and metabolic systems in human body, but also distribute differently in various organs. Fig. 1 is the "map" of selenium in vivo, and it well clarifies the absorption, metabolism and distribution of selenium in the body [9]. It shows the detailed pathways through which selenium obtained from dietary selenocysteine, selenomethionine, methylselenocysteine, selenite, and selenite. The ingested selenium is absorbed from the intestinal lumen potentially involving transport proteins as indicated. It is then converted into hydrogen selenide (H₂Se), and Fig. 1 shows how this intermediate is incorporated into selenoproteins as selenocysteine.

On the other hand, Alzheimer's disease (AD) can cause memory loss as well as the deterioration of thinking and language abilities, thereby leading to a decline in self-care ability and affecting daily life. High levels of depression, anxiety, depression, apathy, and withdrawal symptoms are common for the patients in the early stages of AD, and it later develops into impaired judgment, disorientation, and mental confusion [15, 16]. Severe AD patients often suffer from malnutrition, pulmonary and urinary complications, and die from complications. Taking care of patients with AD demands the utilization of labor, which can impose a significant social burden. Selenium levels were found to be reduced in AD patients, suggesting an important connection between the element and the pathological process of the disease [17]. AD is a neurodegenerative disease characterized by progressive loss of memory and cognitive abilities, along with the impairment of daily activities [18]. It has multiple genetic and environmental risk factors. Early-onset AD can be caused by several autosomal dominant mutations in amyloid precursor protein (APP) and presenilin (PS) 1 and 2 genes [19]. The apolipoprotein E (ApoE) gene has a bearing on sporadic AD risk [20]. Certain environmental factors can also trigger pathological changes in AD, including certain metals, brain damage, dietary defenses, pesticides, and infections [14, 21]. The main pathological features of AD are neuronal death, loss of synaptic connections, amyloid accumulation and neurofibrillary tangles caused by hyperphosphorylated Tau protein deposition [18, 22, 23]. Oxidative stress is widely believed to be a key factor in AD [18]. It interferes with redox signaling and control, resulting in biomolecular damage. Superoxide radicals, hydrogen peroxide, hydroxyl radicals and singlet oxygen are usually fixed reactive oxygen species (ROS) [24, 25]. ROS have detrimental effects on mitochondrial function, synaptic transmission, axonal transport, and stimulation of neuroinflammation [18, 26, 27]. Since antioxidant capacity is an important characteristic of selenium, it may have a direct connection with the treatment of AD. This article will discuss the latest developments in this area.

2. Role of selenoproteins for AD pathology

As a powerful antioxidant, selenium plays a significant role in the treatment of AD. It is an important component of selenoprotein. There are 25 selenoproteins in human body which play active roles in the antioxidant system [28]. They not only protect cells from damaging ROS, but also inhibit lipid peroxidation [29]. Especially, selenium is a vital component of glutathione peroxidase (GPx), which catalyzes hydrogen peroxide and lipid hydrogen peroxide through glutathione metabolism, thus achieving strong antioxidant effect [30, 31]. In the mouse model of AD, selenium has a positive effect on the treatment of AD, mainly by regulating autophagy pathway and synaptic receptor pathway to alleviate Tau protein-induced pathological damage, restore synaptic defects and improve cognitive decline [32, 33]. Therefore, the role of selenium in AD can be reviewed from the role of selenoprotein in AD, the therapeutic effect of selenium supplementation, and the combined effect of selenium and other molecules.

Under normal dietary conditions, selenium levels are highest in the kidneys, followed by liver, spleen, pancreas, heart and brain [34]. However, when selenium is deficient, the priority is to ensure the supply of selenium in the brain to maintain the stability of selenium content in it [11, 35]. Selenium contributes significantly to maintaining the optimal functional state of brain [28]. Fig. 2 shows the sequencing of selenoprotein mRNA levels in the human brain [28]. In mouse brain, GPx4, SELENOK, SELENOM, SELENOW, and SELENOF are the most highly expressed selenoproteins, and GPx4, SELENOP, and SELENOW are expressed in 90% of brain regions [28, 36, 37]. Of the 25 human selenoproteins, six (GPx3, DIO3, GPx2, DIO1, SELENOV, and GPx6) are expressed at very low or almost no levels [28]. High expression levels of SELENOW, GPx4, SELENOP, SELENOF, and SELENOK were almost identical to those observed in mice [36]. Six ER-resident selenoproteins are also expressed at high levels in the brain. They are involved in stress response of endoplasmic reticulum, mainly related to physiological processes such as calcium flux regulation, ubiquitin-protein degradation system, protein folding, redox [28, 38, 39]. In addition, the distribution of selenium proteins in different spaces of the brain also determines their functional differences [28]. Researches have shown that selenoproteins in the brain are mainly concentrated in the hippocampus, olfactory bulb, neocortex, and cerebellar cortex, making it prone to neurodegenerative diseases [36]. The hippocampus and cortex are the main pathological lesions of AD, with abundant GPx4, SELENOW, and SELENOF in these regions [28].

Among human selenoproteins, three selenoprotein subfamilies have been well studied, including selenoproteins, thioredoxin reductase (TrxR), glutathione peroxidase (GPx), and iodothyronine deiodinases (DIO) [14, 40]. The thioredoxin reductases are members of the pyridine nucleotide-disulfide oxidoreductase family. These selenoproteins include TrxR1 (cytoplasmic subtype), TrxR2 (mitochondrial subtype), TrxR3, which are in components of peroxide reduction and are essential for the reduction of thioredoxin (Trx), forming a disulfide bond reductase system with Trx [41-44]. Trx uses cysteine thiol-disulfide exchange to reduce thiol groups in protein residues, which can inhibit apoptosis signaling pathways, regulate apoptosis signal-regulating kinase 1 (ASK1) to prevent apoptosis, and thus control cell division, longevity, and cell death, potentially having a protective effect in AD and epilepsy [14, 43, 44].

Two major members of the DIO family take part in the brain, and they are involved in the synthesis and regulation of thyroid hormones. DIO1 is mainly located in the thyroid, liver, and kidneys, while DIO2 is distributed in the thyroid, brain, pituitary, heart, skeletal muscle, and brown adipose tissue [14, 45, 46]. As an ER selenoprotein, the content of DIO2 in the brain is lower than other proteins [28]. DIO2 in astrocytes can convert T4 into active T3 [14, 46]. Thyroid hormones affect brain development by regulating neuronal and glial cell differentiation, myelin sheath, and synaptic formation [47].

GPx family includes five types of selenoproteins. GPx1 (cytoplasmic), GPx2 (gastrointestinal), GPx3 (plasma) are involved in processes like hydrogen peroxide reduction. GPx4 (phospholipid hydroperoxide glutathione peroxidase) is the strongest antioxidant enzyme in brain among the GPx family selenoproteins, while GPx6 presently exists in olfactory epithelium and embryonic tissues [14, 18, 48]. GPx selenoproteins are expressed in both neurons and glial cells, and through using the antioxidant glutathione as a mechanism, they can reduce peroxides and other reactive oxygen species that may damage cells and tissues [14]. GPx4 is closely related to ferroptosis, which is an iron-dependent programmed cell death [25, 49]. Through the accumulation of iron, the antioxidant system on which glutathione relies cannot function, resulting in a large amount of lipid peroxidation and cell necrosis. It is related to various brain diseases including AD [25, 50]. The lipid peroxidation caused by oxidative stress is an early pathological lesion of AD, and the increase of lipid oxidation level caused by iron drop disease is closely related to the pathological process of AD [28, 29, 51]. GPx4 knockdown cells show no significant change in ROS levels, but the lipid peroxidation levels are significantly increased. Conditional GPx4 knockout mice exhibit extensive neurodegeneration prior to weaning, which may be related to selective loss of microalbumin interneurons in the hippocampus and cortex of mice, confirming the importance of GPx4 in neurodevelopment [28, 52]. GPx1 has not been shown to be directly related to AD, and GPx1 knockout models indicate that deletion of GPx1 leads to increased neuronal sensitivity to Aβ toxicity [53]. GPx2 regulates the balance between intestinal cell regeneration and apoptosis, inhibiting inflammation-induced intestinal carcinogenesis [54]. GPx3 deficiency promotes platelet aggregation, possibly by inhibiting the thromboxane biosynthesis pathway. GPx3 is also considered a tumor suppressor [54].

Selenoprotein P (SELENOP) holds a crucial position among all selenoproteins, and its deficiency leads to a significant decrease in levels of major proteins like GPx4, SELENOK, SELENOM, and SELENOW [28]. Experimental evidences show that selenoproteins P and Aβ and neurofibrillary tangles (NFT) co-localize in the brains of AD patients, suggesting an association between selenoprotein P and AD [55]. Selenoprotein P can influence AD's physiological processes through ApoE. The ApoE4 allele is a significant pathogenic factor in sporadic AD patients [20]. ApoE can transport cholesterol into neuronal cells through LRP1 and LRP8 [20]. The functional changes of LRP1 and LRP8 may be an important cause of AD, leading to reduced cholesterol intake and metabolic issues in the synthesis of copper chaperone apps (amyloid precursor proteins) [56]. Other alleles of ApoE, such as ApoE-ε2 can enhance the proteolysis of Aβ, which may be associated with the pathology of AD [57]. Selenoprotein P has a strong selenium transport function in the human body and is therefore highly expressed in the brain [28]. It promotes selenium absorption by interacting with ApoER2, providing a usable selenium pool [18]. Selenoprotein P, the first selenoprotein found to be associated with synaptic function, is involved in synaptic signaling through interaction with ApoER2 [18, 28]. Besides, it interacts with the C-terminal domain of a-tubulin, which mediates the regulation of microtubule assembly by binding to Tau protein, confirming that it can affect AD through Tau protein pathway [28, 58]. In addition, selenoprotein P, after binding to Aβ and neurofibrillary tangles, may sequester selenium and reduce selenium supply to neurons and glial cells, thereby promoting oxidative stress. Related experiments demonstrated that the Aβ toxicity of selenoprotein P knockout mouse neuroblastoma cells were higher than that of wild type cells [59].

3. Selenium supplementation for the treatment of AD

Selenium is an essential trace element in human metabolism [60]. Excessive or inadequate intake of it may lead to health issues. The World Health Organization has recommended a daily dose of selenium at the level of 50–250 µg for adults [61]. High dosages of selenium intake may be toxic (actually, it depends on the selenium existing form), while insufficient intake of selenium may cause neurological disorders such as AD. In addition, the safe intake range of selenium is relatively narrow [9]. The intake of selenium varies greatly around the world. For example, people in European countries consume < 50 µg of selenium per day (on a per capita basis), which is less than the recommended daily selenium intake [61, 62]. In contrast, people in the United States have a higher intake of food-derived selenium, averaging 133.5 µg/d for men and 92.6 µg/d for women [9]. More than 50% of respondents in the United States take dietary supplements that contain high levels of selenium [63].

According to the statistics, selenium levels in plasma, serum, erythrocyte and cerebrospinal fluid were increased after selenium supplementation, and it may have some effect on the treatment of AD [64]. In addition to selenium levels, the investigations also evaluated malondialdehyde (MDA) levels and GPx activity. MAD is one of the products of lipid peroxide and can be used as an indicator of oxidative stress [65]. Statistics show that no decrease in MDA was observed after selenium supplementation, and some observed an increase, such as an increase observed within a few weeks after supplementation, which may be an adaptive response [64]. GPx activity increases significantly after selenium supplementation, which confirms the increase of selenium level on the other hand [64]. GPx is an important selenoprotein with potential antioxidant activity. It interferes with amyloid and iron neurotoxicity by regulating GPx activity in hippocampal neurons in rats, which appears to have a protective effect on the brain of AD patients [66]. Selenium supplementation improves cognitive performance in AD patients, demonstrating that selenium supplementation does have a positive effect on AD treatment [64].

The main source of selenium in the human body is through food, and about 80% of the dietary selenium can be absorbed [67]. In blood, selenium is mainly transported and absorbed in the form of SEPP1 [68]. Selenium supplementation mainly comes in two forms: organic selenium and inorganic selenium. Organic selenium includes selenomethionine, selenium-enriched yeast and so on, while inorganic selenium includes selenate and selenite. In 3 × Tg-AD mouse model, seleno amino acids, as the main organic form of selenium in vivo, can improve synaptic plasticity and cognitive function of mice by acting on synapses, and have significant effects on AD treatment [69].

In experiments, 3 × Tg-AD mice exhibited larger synaptic gaps and thinner postsynaptic densities, and administration of selenomethionine significantly reduced these defects in the protruding structures [69]. An increase in dendritic spines, a postsynaptic membranous process directly associated with synaptic plasticity, was observed in the synapses of mice treated with selenomethionine [69]. In addition, selenomethionine ameliorates synaptic defects by inhibiting extrasynaptic N-methyl-d-aspartate receptors and stimulating synaptic NMDARs to modulate calcium influx. Selenomethionine treatment upregulated SELENOK levels in AD mice and restored the balance between synaptic and extrasynaptic NMDAR expression [69].

Selenium-enriched yeast is a pure culture of Saccharomyces cerevisiae. It is an important source of selenium supplement. Compared with inorganic selenium, it has less toxicity and higher bioavailability, which has positive effect on AD treatment [70]. The experimental results show that the supplementation of selenium-enriched yeast can improve the learning and memory defects of 3 × Tg-AD mice, improve the selenium level and antioxidant capacity in the brain of mice, and improve synaptic defects. Besides, it can reduce the levels of total Tau protein and hyperphosphorylated Tau protein, regulate brain metabolic function, weaken the activation of glial cells to reduce reaction inflammation, and obviously improve the pathological conditions of AD mice through a series of measures [70]. Dietary selenium-enriched yeast supplementation has a positive effect on AD patients.

In a previous study comparing the effects of selenium-enriched yeast and selenomethionine on 3 × Tg-AD mice, it was found that selenium methionine had a more significant ability to increase selenium levels in various tissues of AD mice than selenium-enriched yeast [71]. However, the improvement effect of selenium-enriched yeast on the cognitive ability of AD mice is better than selenomethionine, which may be related to the various elements and vitamins contained in it [71]. In summary, selenium-enriched yeast has the potential to be used as clinical health products or drugs for AD, but selenomethionine, as a pure organic selenium compound, has a comprehensive effect on AD, and is more suitable for studying the therapeutic mechanism of Se [71].

Se-methylselenocysteine (SMC) is the major selenium compound in selenium rich plants. In terms of mechanism, mitochondrial dysfunction leading to energy metabolism disorders is one of the pathological mechanisms of AD, and SMC treatment improves energy metabolism abnormalities and cognitive impairment via modulating oxidative stress, metal homeostasis, and extracellular signal-regulated kinase activation in 3 × Tg-AD mice [72]. Ebselen, which is also an organoselenium compound, can inhibit oxidative stress in AD model cells and mouse brains by increasing GPx and superoxide dismutase activity, reducing Aβ levels in AD neurons and mouse brains, and the results showed that spatial learning and memory ability of 3 × Tg-AD mice were significantly improved [73].

Selenate is an important source of inorganic selenium supplementation. In the 3 × Tg AD mouse model experiment, supplementation with selenate significantly upregulates the content of a series of proteins that play a role in the pathological process of AD, among which the neurofilament protein skeleton protein is the most affected protein [74]. Among all selenium compounds, sodium selenate at a concentration of 100 µmol/L is completely non-toxic to cells and tissues, so it has great potential as a research drug for selenium supplementation [74]. The increase in serum selenium concentration induced by the super-nutritional sodium selenate supplement is about 10 times higher than that of the nutritional group, indicating a dose-dependent effect on serum selenium concentration [75].

The primary sources of selenium in food encompass grains, meat, dairy products, and the like. Eggs laid by hens typically contain selenium ranging from 3 µg to 25 µg, thereby rendering them an outstanding food source for selenium supplementation. Furthermore, the industry of selenium-rich eggs is experiencing vigorous development on a global scale [9, 76]. Through the utilization of selenium-enriched feed, the selenium content in each egg can be significantly elevated to exceed 50 µg. This enhancement in selenium content not only provides consumers with a more effective means of obtaining this essential nutrient but also showcases the advancements in modern agricultural and livestock production techniques. The development of selenium-rich eggs reflects the continuous pursuit of providing nutritious and high-quality food options to meet the diverse needs of people's health and dietary requirements. It is anticipated that this industry will continue to thrive and innovate, bringing more benefits to both producers and consumers in the future.

4. Combined effects of SE and other biomolecules on AD

Not only does the simple selenium element have an influence on the pathological process of AD, but also other biological substances can cooperate with selenium to exert a combined effect on AD. As an antioxidant, vitamin E has been applied in AD-related research. Experimental results have shown that vitamin E has a positive effect in the treatment of moderate dementia patients [77]. However, other experiments have shown that when combined with an antioxidant cocktail, it fails to improve cognitive performance in people with dementia [78]. In an experiment to prevent AD dementia, long-term supplementation was conducted to see if vitamin E and selenium alone or in combination could prevent new cases of AD or dementia [79]. The results showed that vitamin E and selenium had no significant preventive effect on the incidence of AD. Nevertheless, this is the first large-scale primary prevention trial to investigate the impact of antioxidant supplements on reducing the dementia incidence, which is of great value in medicinal chemistry [79].

Nanoparticles (NPs) are currently a way to treat neurodegenerative diseases. Experiments have shown that under normal circumstances, NPs generally act as oxidants that may cause damage to brain neurons in AD patients, leading to a decline in cognitive function [80-82]. However, nanoparticles can cross the blood-brain barrier (BBB) for targeted drug therapy [82]. The central nervous system has blood-brain barrier, cerebrospinal fluid-blood barrier (avascular arachnoid epithelium) and blood-cerebrospinal fluid barrier (choroid plexus epithelium), which are great challenges for drug treatment of central nervous system. NPs can overcome this problem, and combining NPs with selenium holds great prospects for the treatment of AD [82]. Selenium NPs have low toxicity, high free radical scavenging efficiency and bioavailability. They can inhibit oxidative stress and inflammation due to the strong ability to penetrate cellular tissues [83, 84].

Selenium NPs were found to block the aggregation of Aβ proteins in the anti-AD study [85, 86]. Similarly, chelator-coated selenium NPs have been found in other studies to be effective in preventing Aβ aggregation, memory impairment, and cognitive improvement [82, 87]. It was found that selenium NPs modified by cysteine enantiomers have a strong effect on the aggregation of Aβ in the presence of copper ions and zinc ions [82, 87]. Selenium NPs modified by these chelators can inhibit the formation of Aβ fibrils by binding to metal ion binding sites, and Aβ aggregation is one of the important pathological features of AD [82, 87]. Experimental results have shown that coupling of target peptides to selenium NPs not only crosses the blood-brain barrier, but also inhibit Aβ aggregation [88]. Fig. 3 shows the mechanism of selenium NPs reduction in AD [82].

Folic acid (FA) is an essential part of one carbon unit metabolism, which can promote the conversion of homocysteine (Hcy) to methionine (Met) [89]. High levels of Hcy in the blood are associated with AD, indicating the potential of folate in AD [89, 90]. Fig. 4 shows a schematic diagram of FA metabolism [89]. Experiments have shown that the combined supplementation of selenium and FA can reverse the imbalance of lipid metabolism, which has an important impact on alleviating the pathological process of AD [89]. FA participates in the metabolic cycle of Hcy in the form of tetrahydrofolate, and Se-FA enhances the metabolism from Hcy to Met, thereby reducing the level of Hcy in AD mice [89].

Selenium mainly acts through selenoproteins in the body. In the 3 × Tg AD mouse model, Se-FA supplementation can not only significantly increase selenium levels and the content of major selenoproteins such as GPx and TrxR, but promote the expression of selenoproteins as well [89]. Se-FA significantly reduces approximately 90% of excess lipid metabolites in AD mice and restored the abnormal regulation of lipid metabolism of AD mice to normal. Abnormal serum lipid levels may be a trigger for brain lipid metabolism abnormalities. Experimental results have shown that Se-FA achieves AD resistance to hyperlipidemia by lowering LDL levels and reversing brain lipid peroxidation [89]. Further studies suggested that Se-FA attenuated the pathological changes of Aβ and Tau proteins, by inhibiting BACE1-mediated APP cleavage to reduce Aβ levels, and by enhancing PP2A activity to reduce the hyperphosphorylation of Tau protein, while alleviating two important pathological manifestations of AD [89]. In addition, there is evidence that synaptic dysfunction is an important reason for the cognitive decline in AD. After Se-FA treatment, the levels of related synaptic proteins are elevated, revealing the restorative effect of Se-FA on synaptic plasticity. In mouse models, administration of Se-FA can improve the spatial learning ability of mice [89].

5. Conclusions and perspectives

Due to its strong antioxidant effect, selenium plays a significant physiological role in the pathological process of AD. Selenium exists in the body in the form of selenoprotein, maintaining a relatively constant level in the brain and influencing the pathological process of AD through various pathways. Selenium supplementation has a positive effect on the treatment of AD, and both inorganic and organic selenium are good forms of supplementation. In addition, besides the individual effect of selenium, the combined use with other trace elements or substances can increase the effect of selenium in the body, which is of great help for the treatment of AD.

As an important element closely associated with AD, there are still many unsolved mysteries between selenium and AD. Considering that food is the primary source of selenium intake, developing selenium-enriched agriculture may be an efficient approach for enhancing the health of the residents, thereby preventing AD and certain other diseases [91-94]. As a considerable number of selenium-containing compounds and materials have been identified to play a role in inhibiting agricultural diseases [95-97], the development of dual-effect fertilizers and pesticides constitutes a novel trend in this specific domain [98]. Further investigations are ongoing in our laboratory.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

CRediT authorship contribution statement

Jiajie Gu: Writing – original draft. Jiaxiang Gu: Writing – review & editing, Supervision. Lei Yu: Writing – review & editing, Supervision, Conceptualization.

Acknowledgments

We thank the Yangzhou City and Yangzhou University Cooperation Program (No. YZ2023209), the SeleValley Scholars Basic Research Project (No. 2301) and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) for support. We thank Kaize Liu for assistances in redrawing the figures of this article.