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

Zhang, Zhonghao; Chen, Chen; Jia, Shi-Zheng; Cao, Xian-Chun; Liu, Min; Tian, Jichun; Hoffmann, Peter; Xu, Huaxi; Ni, Jiazuan; Song, Guo-Li

doi:10.1089/ars.2019.7990

Cited by 35 publications

(21 citation statements)

References 68 publications

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“…The same study evaluated brain samples from AD patients and found reduced levels of SELENOK, but not of TrxR1, indicating a correlation between the decreased SELENOK level and AD. Selenomethionine restored synaptic deficits by modulating NMDARs and SELENOK in the brain of the AD mouse model (Zhang et al 2020f ). Table 7 summarizes the animal models of AD in which selenomethionine, diphenyl diselenide, and p -methoxyl-diphenyl diselenide were successfully investigated.…”

Section: Pharmacology Of Organoselenium Compoundsmentioning

confidence: 99%

Toxicology and pharmacology of synthetic organoselenium compounds: an update

2021

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Here, we addressed the pharmacology and toxicology of synthetic organoselenium compounds and some naturally occurring organoselenium amino acids. The use of selenium as a tool in organic synthesis and as a pharmacological agent goes back to the middle of the nineteenth and the beginning of the twentieth centuries. The rediscovery of ebselen and its investigation in clinical trials have motivated the search for new organoselenium molecules with pharmacological properties. Although ebselen and diselenides have some overlapping pharmacological properties, their molecular targets are not identical. However, they have similar anti-inflammatory and antioxidant activities, possibly, via activation of transcription factors, regulating the expression of antioxidant genes. In short, our knowledge about the pharmacological properties of simple organoselenium compounds is still elusive. However, contrary to our early expectations that they could imitate selenoproteins, organoselenium compounds seem to have non-specific modulatory activation of antioxidant pathways and specific inhibitory effects in some thiol-containing proteins. The thiol-oxidizing properties of organoselenium compounds are considered the molecular basis of their chronic toxicity; however, the acute use of organoselenium compounds as inhibitors of specific thiol-containing enzymes can be of therapeutic significance. In summary, the outcomes of the clinical trials of ebselen as a mimetic of lithium or as an inhibitor of SARS-CoV-2 proteases will be important to the field of organoselenium synthesis. The development of computational techniques that could predict rational modifications in the structure of organoselenium compounds to increase their specificity is required to construct a library of thiol-modifying agents with selectivity toward specific target proteins.

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Section: Pharmacology Of Organoselenium Compoundsmentioning

confidence: 99%

Toxicology and pharmacology of synthetic organoselenium compounds: an update

2021

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“…NMDAR is the major receptor for glutamate during neuronal synaptic transmission, and synaptic impairment is directly associated with NMDAR disorders in AD (Wang and Reddy, 2017). Notably, a recent study by Zhang et al (2020) showed imbalanced levels of two functional subunits of NMDAR, namely, NMDAR2A and NMDAR2B, in the brains of SELENOK-knockout mice. Therefore, SELENOK may play a role in neuronal synaptic transmission, but further studies are needed to support this speculation.…”

Section: Synaptic Function and Neurotransmissionmentioning

confidence: 99%

“…However, the direct relationship between SELENOK and AD has not been reported until recently. A study by Zhang et al (2020) showed that SELENOK expression is significantly decreased in the brains of AD patients and mice and that SELENOK knockout is associated with pathological changes, such as intracellular Ca 2+ flux dysregulation in neurons and an imbalance in the distribution of synaptic receptors, that are highly consistent with AD pathology. Currently, neuronal excitotoxicity mediated by the disequilibrium between synaptic and extrasynaptic NMDAR is a widely accepted pathogenic factor for synaptic loss in AD (Hardingham and Bading, 2010;Talantova et al, 2013;Huang et al, 2017).…”

Section: Selenok Selenot Selenos and Selenommentioning

confidence: 99%

Roles of Selenoproteins in Brain Function and the Potential Mechanism of Selenium in Alzheimer’s Disease

Zhang

Song

2021

Front. Neurosci.

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Selenium (Se) and its compounds have been reported to have great potential in the prevention and treatment of Alzheimer’s disease (AD). However, little is known about the functional mechanism of Se in these processes, limiting its further clinical application. Se exerts its biological functions mainly through selenoproteins, which play vital roles in maintaining optimal brain function. Therefore, selenoproteins, especially brain function-associated selenoproteins, may be involved in the pathogenesis of AD. Here, we analyze the expression and distribution of 25 selenoproteins in the brain and summarize the relationships between selenoproteins and brain function by reviewing recent literature and information contained in relevant databases to identify selenoproteins (GPX4, SELENOP, SELENOK, SELENOT, GPX1, SELENOM, SELENOS, and SELENOW) that are highly expressed specifically in AD-related brain regions and closely associated with brain function. Finally, the potential functions of these selenoproteins in AD are discussed, for example, the function of GPX4 in ferroptosis and the effects of the endoplasmic reticulum (ER)-resident protein SELENOK on Ca2+ homeostasis and receptor-mediated synaptic functions. This review discusses selenoproteins that are closely associated with brain function and the relevant pathways of their involvement in AD pathology to provide new directions for research on the mechanism of Se in AD.

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“…There is a rich literature on mouse models of neurodegenerative diseases whose phenotypes can be exacerbated by additional deficiency of "antioxidant" selenoproteins (Schweizer et al, 2004a;Zhang et al, 2020). In such models there is always the conceptual question whether the mutation in the selenoprotein specifically abrogates (and thus reveals) a specific protective mechanism or whether the selenoprotein mutation simply tips over a dysbalanced system that is already vulnerable to any other possible stressor.…”

Section: Genetic Deficiency Of Single Selenoproteinsmentioning

confidence: 99%

The Neurobiology of Selenium: Looking Back and to the Future

et al. 2021

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Eighteen years ago, unexpected epileptic seizures in Selenop-knockout mice pointed to a potentially novel, possibly underestimated, and previously difficult to study role of selenium (Se) in the mammalian brain. This mouse model was the key to open the field of molecular mechanisms, i.e., to delineate the roles of selenium and individual selenoproteins in the brain, and answer specific questions like: how does Se enter the brain; which processes and which cell types are dependent on selenoproteins; and, what are the individual roles of selenoproteins in the brain? Many of these questions have been answered and much progress is being made to fill remaining gaps. Mouse and human genetics have together boosted the field tremendously, in addition to traditional biochemistry and cell biology. As always, new questions have become apparent or more pressing with solving older questions. We will briefly summarize what we know about selenoproteins in the human brain, glance over to the mouse as a useful model, and then discuss new questions and directions the field might take in the next 18 years.

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

Cited by 35 publications

References 68 publications

Toxicology and pharmacology of synthetic organoselenium compounds: an update

Toxicology and pharmacology of synthetic organoselenium compounds: an update

Roles of Selenoproteins in Brain Function and the Potential Mechanism of Selenium in Alzheimer’s Disease

The Neurobiology of Selenium: Looking Back and to the Future

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