Transcriptomic Insights into the Response of the Olfactory Bulb to Selenium Treatment in a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by the presence of extracellular senile plaques primarily composed of Aß peptides and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau proteins. Olfactory dysfunction is an early clinical phenotype in AD and was reported to be attributable to the presence of NFTs, senile Aß plaques in the olfactory bulb (OB). Our previous research found that selenomethionine (Se-Met), a major form of selenium (Se) in organisms, effectively increased oxidation resistance as well as reduced the generation and deposition of Aß and tau hyperphosphorylation in the olfactory bulb of a triple transgenic mouse model of AD (3×Tg-AD), thereby suggesting a potential therapeutic option for AD. In this study, we further investigated changes in the transcriptome data of olfactory bulb tissues of 7-month-old triple transgenic AD (3×Tg-AD) mice treated with Se-Met (6 µg/mL) for three months. Comparison of the gene expression profile between Se-Met-treated and control mice revealed 143 differentially expressed genes (DEGs). Among these genes, 21 DEGs were upregulated and 122 downregulated. The DEGs were then annotated against the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. The results show that upregulated genes can be roughly classified into three types. Some of them mainly regulate the regeneration of nerves, such as Fabp7, Evt5 and Gal; some are involved in improving cognition and memory, such as Areg; and some are involved in anti-oxidative stress and anti-apoptosis, such as Adcyap1 and Scg2. The downregulated genes are mainly associated with inflammation and apoptosis, such as Lrg1, Scgb3a1 and Pglyrp1. The reliability of the transcriptomic data was validated by quantitative real time polymerase chain reaction (qRT-PCR) for the selected genes. These results were in line with our previous study, which indicated therapeutic effects of Se-Met on AD mice, providing a theoretical basis for further study of the treatment of AD by Se-Met.

Selenomethionine Mitigates Cognitive Decline by Targeting Both Tau Hyperphosphorylation and Autophagic Clearance in an Alzheimer's Disease Mouse Model.

Tau pathology was recently identified as a key driver of disease progression and an attractive therapeutic target in Alzheimer's disease (AD). Selenomethionine (Se-Met), a major bioactive form of selenium (Se) in organisms with significant antioxidant capacity, reduced the levels of total tau and hyperphosphorylated tau and ameliorated cognitive deficits in younger triple transgenic AD (3xTg-AD) mice. Whether Se-Met has a similar effect on tau pathology and the specific mechanism of action in older 3xTg-AD mice remains unknown. Autophagy is a major self-degradative process to maintain cellular homeostasis and function. Autophagic dysfunction has been implicated in the pathogenesis of multiple age-dependent diseases, including AD. Modulation of autophagy has been shown to retard the accumulation of misfolded and aggregated proteins and to delay the progression of AD. Here, we found that 3xTg-AD mice showed significant improvement in cognitive ability after a 3-month treatment with Se-Met beginning at 8 months of age. In addition to attenuating the hyperphosphorylation of tau by modulating the activity of Akt/glycogen synthase kinase-3ß and protein phosphatase 2A, Se-Met-induced reduction of tau was also mediated by an autophagy-based pathway. Specifically, Se-Met improved the initiation of autophagy via the AMP-activated protein kinase-mTOR (mammalian target of rapamycin) signaling pathway and enhanced autophagic flux to promote the clearance of tau in 3xTg-AD mice and primary 3xTg neurons. Thus, our results demonstrate for the first time that Se-Met mitigates cognitive decline by targeting both the hyperphosphorylation of tau and the autophagic clearance of tau in AD mice. These data strongly support Se-Met as a potent nutraceutical for AD therapy.SIGNIFICANCE STATEMENT Selenium has been widely recognized as a vital trace element abundant in the brain with effects of antioxidant, anticancer, and anti-inflammation. In this study, we report that selenomethionine rescues spatial learning and memory impairments in aged 3xTg-AD mice via decreasing the level of tau protein and tau hyperphosphorylation. We find that selenomethionine promotes the initiation of autophagy via the AMPK-mTOR pathway and enhances autophagic flux, thereby facilitating tau clearance in vivo and in vitro We have now identified an additional, novel mechanism by which selenomethionine improves the cognitive function of AD mice. Specifically, our data suggest the effect of selenium/selenomethionine on an autophagic pathway in Alzheimer's disease.

Selenomethionine promoted hippocampal neurogenesis via the PI3K-Akt-GSK3ß-Wnt pathway in a mouse model of Alzheimer's disease.

The maintenance of neural system integrity and function is the ultimate goal for the treatment of neurodegenerative disease such as Alzheimer's disease (AD). Neurogenesis plays an integral role in the maintenance of neural and cognitive functions, and its dysfunction is regarded as a major cause of cognitive impairment in AD. Moreover, the induction of neurogenesis by targeting endogenous neural stem cells (NSCs) is considered as one of the most promising treatment strategies. Our previous studies demonstrated that selenomethionine (Se-Met) was able to reduce ß-amyloid peptide (Aß) deposition, decrease Tau protein hyperphosphorylation and markedly improve cognitive functions in triple transgenic (3xTg) AD mice. In this study, we reported that the therapeutic effect of Se-Met on AD could also be due to neurogenesis modulation. By using the cultured hippocampal NSCs from 3xTg AD mice, we discovered that Se-Met (1-10 µM) with low concentration could promote NSC proliferation, while the one with a high concentration (50,100 µM) inhibiting proliferation. In subsequent studies, we also found that Se-Met activated the signaling pathway of PI3K/Akt, and thereby inhibited the GSK3ß activity, which would further activated the ß-catenin/Cyclin-D signaling pathway and promote NSC proliferation. Besides, after the induction of Se-Met, the number of neurons differentiated from NSCs significantly increased, and the number of astrocytes decreased. After a 90-day treatment with Se-Met (6 µg/mL), the number of hippocampal neurons in 4-month-old AD mice increased significantly, while the one of astrocyte saw a sharp drop. Thus, Se-Met treatment promoted NSCs differentiation into neurons, and subsequently repaired damaged neural systems in AD mice. Being consistent with our in vitro studies, Se-Met acts through the PI3K-Akt- GSK3ß-Wnt signaling pathway in vivo. This study provides an unparalleled evidence that selenium (Se) compounds are, to some extent, effective in promoting neurogenesis, and therefore we propose a novel mechanism for Se-Met treatment in AD.

Selenomethionine Ameliorates Neuropathology in the Olfactory Bulb of a Triple Transgenic Mouse Model of Alzheimer's Disease.

Olfactory dysfunction is an early and common symptom in Alzheimer's disease (AD) and is reported to be related to several pathologic changes, including the deposition of Aß and hyperphosphorylated tau protein as well as synaptic impairment. Selenomethionine (Se-Met), the major form of selenium in animals and humans, may be a promising therapeutic option for AD as it decreases the deposition of Aß and tau hyperphosphorylation in a triple transgenic mouse model of AD (3× Tg-AD). In this study, 4-month-old AD mice were treated with 6 µg/mL Se-Met in drinking water for 12 weeks and the effect of Se-Met on neuropathological deficits in olfactory bulb (OB) of 3× Tg-AD mice was investigated. The administration of Se-Met effectively decreased the production and deposition of Aß by inhibiting ß-site amyloid precursor protein cleaving enzyme 1 (BACE1)-regulated amyloid precursor protein (APP) processing and reduced the level of total tau and phosphorylated tau, which depended on depressing the activity and expression of glycogen synthase kinase-3ß (GSK-3ß) and cyclin-dependent kinase 5 (CDK5). Meanwhile, Se-Met reduced glial activation, relieved neuroinflammation and attenuated neuronal cell death in the OB of AD mice. So Se-Met could improve pathologic changes of AD in the OB, which further demonstrated the potential therapeutic effect of Se-Met in AD.

Computational identification of a new SelD-like family that may participate in sulfur metabolism in hyperthermophilic sulfur-reducing archaea.

BACKGROUND: Selenium (Se) and sulfur (S) are closely related elements that exhibit similar chemical properties. Some genes related to S metabolism are also involved in Se utilization in many organisms. However, the evolutionary relationship between the two utilization traits is unclear. RESULTS: In this study, we conducted a comparative analysis of the selenophosphate synthetase (SelD) family, a key protein for all known Se utilization traits, in all sequenced archaea. Our search showed a very limited distribution of SelD and Se utilization in this kingdom. Interestingly, a SelD-like protein was detected in two orders of Crenarchaeota: Sulfolobales and Thermoproteales. Sequence and phylogenetic analyses revealed that SelD-like protein contains the same domain and conserved functional residues as those of SelD, and might be involved in S metabolism in these S-reducing organisms. Further genome-wide analysis of patterns of gene occurrence in different thermoproteales suggested that several genes, including SirA-like, Prx-like and adenylylsulfate reductase, were strongly related to SelD-like gene. Based on these findings, we proposed a simple model wherein SelD-like may play an important role in the biosynthesis of certain thiophosphate compound. CONCLUSIONS: Our data suggest novel genes involved in S metabolism in hyperthermophilic S-reducing archaea, and may provide a new window for understanding the complex relationship between Se and S metabolism in archaea.

Different Forms of Selenoprotein M Differentially Affect Aß Aggregation and ROS Generation.

Selenoprotein M (SelM), one of the executants of selenium in vivo, is highly expressed in human brain and most probably involved in antioxidation, neuroprotection, and intracellular calcium regulation, which are the key factors for preventing the onset and progression of Alzheimer's disease (AD). In this paper, human SelM was successfully overexpressed in human embryonic kidney cells HEK293T. Sodium selenite (Na(2)SeO(3) 0.5 µmol/L) increased the expression of full-length SelM and inhibited the expression of truncated SelM. The full-length SelM exhibited higher antioxidant activity than its selenocysteine-to-cysteine mutation form SelM', whereas the truncated SelM had an adverse effect that increased the oxidative stress level of cells. When ß-amyloid (Aß(42), an AD relevant peptide) was cotransfected with the empty expression vector, SelM, or SelM' under the induction of 0.5 µmol/L Na(2)SeO(3), the intracellular Aß(42) aggregation rates were detected to be 57.9% ± 5.5%, or 22.3% ± 2.6%, or 26.3% ± 2.1%, respectively, showing the inhibitory effects on Aß aggregation by the full-length SelM and SelM'. Meanwhile, the intumescentia of mitochondria caused by Aß(42) transfection was significantly mitigated by the cotransfection of SelM or SelM' with Aß(42) under the induction of 0.5 µmol/L Na(2)SeO(3). On the contrary, cotransfection of SelM and Aß(42) without the induction of Na(2)SeO(3) increased Aß(42) aggregation rate to 65.1% ± 3.2%, and it could not inhibit the Aß-induced intumescent mitochondria. In conclusion, full-length SelM and SelM¢ might prevent Aß aggregation by resisting oxidative stress generated during the formation of Aß oligomers in cells.

Fabrication of novel hierarchical structured Fe3O4 @LnPO4 (Ln=Eu, Tb, Er) multifunctional microspheres for capturing and labeling phosphopeptides.

Novel core-shell structured Fe3O4@LnPO4 (Ln=Eu, Tb, Er) multifunctional microspheres with a magnetic Fe3O4 core and a LnPO4 shell covered with spikes are synthesized for the first time through the combination of a homogeneous precipitation approach and an ion-exchange process. Their potential for selective capture, rapid separation, and easy mass spectrometry (MS) labeling of the phosphopeptides from complex proteolytic digests are evaluated. These affinity microspheres can improve the specificity for capture of the phosphopeptides, realize fast magnetic separation, enhance the MS detection signals, and directly identify phosphopeptides through 80 Da mass loss in the mass spectra. The synthesis strategy could become a general and effective technique for similar core-shell hierarchical structures.

Monodisperse REPO4 (RE = Yb, Gd, Y) hollow microspheres covered with nanothorns as affinity probes for selectively capturing and labeling phosphopeptides.

Rare-earth phosphate microspheres with unique structures were developed as affinity probes for the selective capture and tagging of phosphopeptides. Prickly REPO(4) (RE = Yb, Gd, Y) monodisperse microspheres, that have hollow structures, low densities, high specific surface areas, and large adsorptive capacities were prepared by an ion-exchange method. The elemental compositions and crystal structures of these affinity probes were confirmed by energy-dispersive spectroscopy (EDS), powder X-ray diffraction (XRD), and Fourier-transform infrared (FTIR) spectroscopy. The morphologies of these compounds were investigated using scanning electron microscopy (SEM), transmission electron microscopy (TEM), and nitrogen-adsorption isotherms. The potential ability of these microspheres for selectively capturing and labeling target biological molecules was evaluated by using protein-digestion analysis and a real sample as well as by comparison with the widely used TiO(2) affinity microspheres. These results show that these porous rare-earth phosphate microspheres are highly promising probes for the rapid purification and recognition of phosphopeptides.

A facile fabrication of spherical and beanpod-like magnetic-fluorescent particles with targeting functionalities.

Magnetic-fluorescent particles with targeting functionalities were fabricated by a modified Stöber method and two shapes (spherical and beanpod-like) were obtained by simply tuning the reaction temperature. The two multifunctional probes combined the useful functions of magnetism, fluorescence and FA (folic acid)-targeting recognition into one entity. The products were characterized by scanning electron microscopy, transmission electron microscopy, photoluminescence spectroscopy, confocal laser scanning microscopy, by a superconducting quantum interference device and by Fourier transform infrared spectroscopy. The experimental results show that the products possessed rapid magnetic response, relatively strong fluorescent signal, higher photostability and FA-targeting recognition as well as good water-dispersibility, suggesting that they would have potential medical applications in biolabeling and bioimaging.

Lanthanum silicate coated magnetic microspheres as a promising affinity material for phosphopeptide enrichment and identification.

Novel Fe(3)O(4)@La(x)Si(y)O(5) affinity microspheres consisting of a superparamagnetic Fe(3)O(4) core and an amorphous lanthanum silicate shell have been synthesized. The core-shell-structured Fe(3)O(4)@La(x)Si(y)O(5) microspheres, with a mean size of ca. 480 nm, had rough lanthanum silicate surfaces and displayed relatively strong magnetism (47.2 emu g(-1)). This novel affinity material can be used for selective capture, rapid magnetic separation, and part dephosphorylation (which plays an important role in identifying phosphopeptides in MS) of the phosphopeptides in a peptide mixture. Its ability to selectively trap and magnetically isolate as well as label the phosphopeptides was evaluated using a standard phosphorylated protein (ß-casein) and a real sample (human serum). Phosphopeptides and their corresponding label ions were detected for concentrations of ß-casein as low as 1 × 10(-9) M and in mixtures of ß-casein and BSA with molar ratios as low as 1:50. In addition, this affinity material, with its labeling properties, is superior to commercial TiO(2) beads in terms of interference from non-phosphopeptide molecules. These results reveal that the lanthanum silicate coated magnetic microspheres represent a promising affinity material for the rapid purification and recognition of phosphopeptides.

Reversal of Lipid Metabolism Dysregulation by Selenium and Folic Acid Co-Supplementation to Mitigate Pathology in Alzheimer's Disease.

Aberrant lipid metabolism is reported to be closely related to the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD). Selenium (Se) and folate are two ideal and safe nutritional supplements, whose biological effects include regulating redox and homocysteine (Hcy) homeostasis in vivo. Here, to achieve effective multitarget therapy for AD, we combined Se and folic acid in a co-supplementation regimen (Se-FA) to study the therapeutic potential and exact mechanism in two transgenic mouse models of AD (APP/Tau/PSEN and APP/PS1). In addition to a reduction in Aß generation and tau hyperphosphorylation, a restoration of synaptic plasticity and cognitive ability was observed in AD mice upon Se-FA administration. Importantly, by using untargeted metabolomics, we found that these improvements were dependent on the modulation of brain lipid metabolism, which may be associated with an antioxidant effect and the promotion of Hcy metabolism. Thus, from mechanism to effects, this study systematically investigated Se-FA as an intervention for AD, providing important mechanistic insights to inform its potential use in clinical trials.

Metabolomic profiles delineate potential roles for gadolinium chloride in the proliferation or inhibition of Hela cells.

Lanthanides (Lns) compounds have been reported to possess contrary effects on cell activity, i.e., promoting cell cycle progression and cell growth by lower concentration treatment, but suppressing cell proliferation and inducing cell apoptosis at higher dosing. However, the cellular processes during the intervention and the possible underlying mechanisms are still not well clarified. Using a combination of high-throughput liquid chromatography (LC) with mass spectrometry (MS), we have investigated the metabolomic profiles of Hela cells following gadolinium chloride (GdCl(3)) treatment in time- and concentration- dependent manners. A total of 48 metabolites released by Hela cells are identified to be differentially expressed (P < 0.05) in different states. Metabolic pathways analyses reveal that the differential metabolites are mainly characterized by increased lipid and amino acid metabolisms and by decreased lipid, amino acid, and carbohydrate metabolisms for cells treated with GdCl(3) at lower and higher concentrations, respectively. Notably, in the higher level GdCl(3) case, the down-expressions of metabolites are predominantly in the glycolytic and the redox pathways. The above results, obtained by using a metabolomic strategy for the first time, disclose that different cell signaling pathways are activated by GdCl(3) treatment with different concentrations, leading to inhibitory or promotional effect on Hela cells.

Synthesis and characterization of [Eu(DBM)3phen]Cl3 @ SiO2-NH2 composite nanoparticles.

Fluorescent rare earth complex Eu(DBM)3(phen)]Cl3@SiO2-NH2 nanoparticles were synthesized by combination of solvent precipitation method and Stöber method. The morphologies, structure, surface and optical properties of the samples were characterized by field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), fourier transform infrared (FTIR) spectroscopy, thermal gravimetric analysis (TGA), differential scanning calorimetry (DSC), and fluorescence spectrophotometer (FS). The observation from FE-SEM images indicate that the obtained samples are spherical and uniform nanoparticles with a tunable average sizes from 140 nm to 300 nm. TEM results verify a core-shell structure of the nanoparticles. The FTIR spectrum confirms the characteristic vibration absorption peaks of the complex [Eu(DBM)3(phen)]Cl3@SiO2-NH2. TGA result indicates that the complex is stable below 200 degrees C. The photoluminescence analysis shows that the complex has Eu3+ characteristic red luminescence and broader excitation peak from 200 nm to 450 nm that can meet the demands of fluorescent confocal imaging. The amino groups are directly introduced to the [Eu(DBM)3(phen)]Cl3@SiO2-NH2 nanoparticles surface by using APS (3-aminopropyl triethoxysilane). This makes the surface modification and bioconjugation of the nanoparticles easier. The nano-sized spheres could be provided a basis for further expansion of its application in biomedical imaging, biological detection and fluorescent nanoprobes.

Synthesis of the Fe3O4@SiO2@SiO2-Tb(PABA)3 luminomagnetic microspheres.

In this paper, we describe the synthesis and characterization of a luminomagnetic microspheres with core-shell structures (denoted as Fe3O4@ SiO2 @SiO2-Tb(PABA)3). The luminomagnetic microspheres were characterized by field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR), vibrating sample magnetometer (VSM), and photoluminescence spectrophotometer (PL). The SEM observation shows that the microsphere consists of the magnetic core with about 400 nm in average diameter and silica shell doped with terbium complex with an average thickness of about 90 nm. It has a saturation magnetization of 15.8 emu/g and a negligible coercivity at room temperature and exhibits strong green emission peak from 5D4 --> 7F5 transition of Tb3+ ions. The luminomagnetic microspheres with good magnetic response and fluorescence probe property as well as water-dispersibility would have potential medical applications, such as time-resolved fluoroimmunoassay (TR-FIA), fluorescent imaging, and magnetic resonance imaging (MRI).

Selenium Restores Synaptic Deficits by Modulating NMDA Receptors and Selenoprotein K in an Alzheimer's Disease Model.

Aims: Strong evidence has implicated synaptic failure as a direct contributor to cognitive decline in Alzheimer's disease (AD), and selenium (Se) supplementation has demonstrated potential for AD treatment. However, the exact roles of Se and related selenoproteins in mitigating synaptic deficits remain unclear. Results: Our data show that selenomethionine (Se-Met), as the major organic form of Se in vivo, structurally restored synapses, dendrites, and spines, leading to improved synaptic plasticity and cognitive function in triple transgenic AD (3 × Tg-AD) mice. Furthermore, we found that Se-Met ameliorated synaptic deficits by inhibiting extrasynaptic N-methyl-d-aspartate acid receptors (NMDARs) and stimulating synaptic NMDARs, thereby modulating calcium ion (Ca2+) influx. We observed that a decrease in selenoprotein K (SELENOK) levels was closely related to AD, and a similar disequilibrium was found between synaptic and extrasynaptic NMDARs in SELENOK knockout mice and AD mice. Se-Met treatment upregulated SELENOK levels and restored the balance between synaptic and extrasynaptic NMDAR expression in AD mice. Innovation: These findings establish a key signaling pathway linking SELENOK and NMDARs with synaptic plasticity regulated by Se-Met, and thereby provide insight into mechanisms by which Se compounds mediate synaptic deficits in AD. Conclusion: Our study demonstrates that Se-Met restores synaptic deficits through modulating Ca2+ influx mediated by synaptic and extrasynaptic NMDARs in 3 × Tg-AD mice, and suggests a potentially functional interaction between SELENOK and NMDARs. Antioxid. Redox Signal. 35, 863-884.

[A differential proteomic study on the influence of ytterbium citrate on HepG2 cells].

OBJECTIVE: To explore the effects of ytterbium citrate on human liver carcinoma HepG2 cell line and the potential mechanisms. METHODS: The HepG2 cells were cultured with DMEM medium and divided into different groups in the following media, in serum-free medium as control, different concentration (0.01 - 5.00 mmol/L) [YbCit(2)](3-)+serum-free medium as treatment group, MTT assay was used to measure the viability of the cells; 2.00 mmol/L [YbCit(2)](3-)+serum-free medium was used as treatment group, and Hoechst 33258 staining was used to detect apoptosis in HepG2 cells. Differential proteomic analysis, assay of intracellular H(2)O(2) levels and mitochondrial transmembrane potential were performed to study the effects of [YbCit(2)](3-) on HepG2 cells and the potential mechanisms. RESULTS: The data showed that 72 h treatment of [YbCit(2)](3-) at 2.00 - 5.00 mmol/L significantly inhibited cell proliferation, and the IC(50) was (2.46 ± 0.23) mmol/L. After treatment with 2.00 mmol/L [YbCit(2)](3-) for 48 h and 72 h, Hoechst 33258 staining demonstrated that [YbCit(2)](3-) induced significantly increased apoptosis in HepG2 cells. After treatment with 2.00 mmol/L [YbCit(2)](3-) for 72 h, two dimensional gel electrophoresis and MALDI-TOF mass spectrometry analysis revealed 14 differentially expressed proteins between [YbCit(2)](3-)-treated cells and the control cells. These proteins mainly included cofilin1, peroxiredoxin6, S100 calcium-binding protein A6, and proteasome 26S non-ATPase subunit 13 isoform 3 and so on. These proteins played important roles in the processes of anti-apoptosis, oxidation reduction, cell proliferation and protein degradation. The mitochondrial membrane potential were investigated, the results showed the red and green fluorescence ratio was 2.45 ± 0.28 in the control group, 1.56 ± 0.23 in 24 h group, 1.16 ± 0.18 in 48 h group, compared with the control, the differences were significant (F = 23.97, P = 0.001). The results of H(2)O(2) detection showed the fluorescence intensity was 20.00 ± 2.08 in the control group, 40.00 ± 5.50 in 24 h group, and 48.00 ± 2.03 in 48 h group, compared with the control, the differences were significant (F = 48.40, P = 0.000). The results indicated a significant reduction in mitochondrial transmembrane potential and significant increase in H2O2 generation were observed in [YbCit(2)](3-)-treated cells. CONCLUSION: These results suggested that [YbCit(2)](3-) could induce apoptosis of HepG2 cells through the mechanisms involving oxidative stress and mitochondrial dysfunction.

Comparative Serum Proteomic Analysis of the Effects of Sodium Selenate on a Mouse Model of Alzheimer's Disease.

Selenium (Se), as a nutritionally essential trace element, has been shown to decrease with age and is closely related to Alzheimer's disease (AD). To probe the effects of Se on AD pathology, two-dimensional fluorescence difference gel electrophoresis was applied to the serum samples collected from the wild-type (WT) mice and the triple transgenic (PS1M146V/AßPPSwe/TauP301L) AD mice (3xTg-AD), treated with or without sodium selenate in drinking water for 4 months beginning at 2 months of age. Proteomics results revealed 17 differentially expressed proteins between WT and 3xTg-AD mice. It was found that the administration of selenate reversed the alterations of the differentially expressed serum proteins by up-regulating 13 proteins and down-regulating 2 proteins which were reported to be involved in the key pathogenesis of AD, including regulation of Aß production, lipid metabolism regulation, and anti-inflammation. These results suggested that a dietary supplement with selenate is effective for prevention and treatment of AD, and the mechanism was maybe related to its role in Aß regulation, lipid metabolism, and anti-inflammation. Moreover, we also presented that α-2 macroglobulin, transthyretin, haptoglobin, alpha-2-HS-glycoprotein, and alpha-1-antitrypsin in the serum can be used to evaluate the effect of selenate on AD pathology.

Comparison of the effects of selenomethionine and selenium-enriched yeast in the triple-transgenic mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disease that exhibits multiple pathogeneses and heterogeneity. Selenium (Se) is an essential trace element for human and animal nutrition. It has been shown that supplementation with two organic forms of Se, Se-enriched yeast (Se-yeast) and selenomethionine (Se-Met), could improve cognitive impairment, reverse synaptic deficits and mitigate tau pathology in triple-transgenic (3× Tg) AD mice. Se-yeast is well known for its high Se-Met content, which may mediate its anti-AD effects. In addition, a large amount of the physiological and biochemical mechanisms of these two Se drugs in the amelioration AD pathology remains unknown. In this study, the content of Se-yeast aside from Se was analyzed, and the effects of Se-Met and Se-yeast on 3× Tg-AD mice were investigated and compared. The results showed that both Se-Met and Se-yeast not only significantly increased the Se levels, enhanced the antioxidant capacity and improved the cognitive decline in the model, but also decreased the Aß and tau pathologies in the brain tissue of the AD mice. Moreover, the ability of Se-Met to increase the Se levels in different tissues of the AD mice was more significant than that of Se-yeast. However, the positive effect of Se-yeast on improving the cognitive ability of the AD mice was better than that of Se-Met, likely due to the various elements, vitamins and other nutrients in Se-yeast. Collectively, these results suggest that Se-yeast has potential as a clinical health product or drug for AD but that Se-Met, as a pure organic Se compound, is more suitable for studying the therapeutic mechanism of Se because of its comprehensive effects on AD.

Selenium-enriched yeast inhibited ß-amyloid production and modulated autophagy in a triple transgenic mouse model of Alzheimer's disease.

As the most common cause of progressive intellectual failure in elderly humans, Alzheimer's disease (AD) is pathologically featured by amyloid plaques, synaptic loss, and neurofibrillary tangles. The amyloid plaques are mainly aggregates of amyloid ß-peptide (Aß), a primary factor contributing to the pathogenesis of AD. Elimination or reduction of the level of Aß is considered an important strategy in AD treatment. The pharmacotherapeutic efficacy of selenium (Se), an essential biological trace element for mammalian species, has been confirmed in a number of experimental models of neurodegenerative diseases. Selenium-enriched yeast (Se-yeast) is commonly used as a nutritional supplement for Se. In this study, we investigated the effects and underlying mechanisms of Se-yeast on Aß pathology in a 4-month-old triple transgenic mouse model of AD (3×Tg-AD mice). The administration of Se-yeast attenuated the deposition of Aß in the brains of AD mice, which was concomitant with decreased levels of LC3II. The Se-yeast treatment decreased the level of amyloid-protein precursor (APP), downregulated the activity of AMP-activated protein kinase (AMPK) and upregulated the activity of AKT/mTOR/p70S6K. Furthermore, the levels of p62 also significantly decreased, and the cathepsin D levels increased, accompanied by increased turnover of Aß and APP in Se-yeast-treated AD mice. In addition to decreasing the generation of Aß, Se-yeast also inhibited the initiation of autophagy by modulating the AMPK/AKT/mTOR/p70S6K signaling pathway and enhanced autophagic clearance, thus reducing the burden of Aß accumulation in the brains of AD mice. Our results further highlight the potential therapeutic effects of Se-yeast on AD.

Long-Term Dietary Supplementation with Selenium-Enriched Yeast Improves Cognitive Impairment, Reverses Synaptic Deficits, and Mitigates Tau Pathology in a Triple Transgenic Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by multiple histopathological changes in the brain and by impairments in memory and cognitive function. Currently, there is no effective treatment that can halt or reverse the progression of this disease. Here, we explored the effects of 3 months of treatment with selenium-enriched yeast (Se-yeast), which is commonly used as a source of organic selenium (Se) for nutrition, on cognitive dysfunction and neuropathology in the triple transgenic mouse model of AD (3×Tg-AD mice). As the results revealed that Se-yeast significantly improved the spatial learning and memory retention of 3×Tg-AD mice, promoted neuronal activity, attenuated the activation of astrocytes and microglia, mitigated synaptic deficits, and reduced the levels of total tau and phosphorylated tau though inhibiting the activity of GSK-3ß, dietary supplementation with Se-yeast exerted multiple beneficial effects on the prevention or treatment of AD. These findings provide evidence of a potentially viable compound for AD treatment.