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.

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.

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.