Elsevier

Free Radical Biology and Medicine

Volume 127, 1 November 2018, Pages 124-133
Free Radical Biology and Medicine

Review Article
Selenium, selenoprotein P, and Alzheimer's disease: is there a link?

https://doi.org/10.1016/j.freeradbiomed.2018.02.030Get rights and content

Highlights

  • Se is crucial to the brain; its deprivation causes irreversible damage to neuronal tissue.

  • SELENOP delivers Se to the brain by binding to a surface receptor, ApoER2.

  • SELENOP is strongly linked to hallmarks of AD (Aβ plaques and neurofibrillary tangles).

  • Studies indicate a beneficial effect of Se and SELENOP in cognition and AD pathology.

  • SELENOP binds redox-active metals in the brain, providing neuroprotection.

Abstract

The essential trace element, selenium (Se), is crucial to the brain but it may be potentially neurotoxic, depending on dosage and speciation; Se has been discussed for decades in relation to Alzheimer's disease (AD). Selenoprotein P (SELENOP) is a secreted heparin-binding glycoprotein which serves as the main Se transport protein in mammals. In vivo studies showed that this protein might have additional functions such as a contribution to redox regulation. The current review focuses on recent research on the possible role of SELENOP in AD pathology, based on model and human studies. The review also briefly summarizes results of epidemiological studies on Se supplementation in relation to brain diseases, including PREADViSE, EVA, and AIBL. Although mainly positive effects of Se are assessed in this review, possible detrimental effects of Se supplementation or exposure, including potential neurotoxicity, are also mentioned. In relation to AD, various roles of SELENOP are discussed, i.e. as the means of Se delivery to neurons, as an antioxidant, in cytoskeleton assembly, in interaction with redox-active metals (copper, iron, and mercury) and with misfolded proteins (amyloid-beta and hyperphosphorylated tau-protein).

Introduction

Selenoprotein P (SELENOP [1], also known as SelP, SePP, SePP1, and SeP) is one of 25 human selenoproteins [2] containing the 21st proteinogenic amino acid selenocysteine (Sec). SELENOP is the sole human selenoprotein that can contain up to ten Sec residues [3], [4] and is considered to be the main selenium (Se) transport protein in mammals [5]. Se is a trace element essential for humans that, while being crucial to the brain, can also be highly neurotoxic depending on dosage and speciation [4], [6], [7]. Although the content of Se in the brain is only some 2.3% of the total amount of Se in the human body [8], the brain is highly protected from Se depletion owing to the hierarchical structure of Se metabolism [9]. The region-specific pattern for brain Se deposition has been found using radioactive 75Se-labeled selenite. The brain uptake of labeled 75Se-selenite was shown to start only after the appearance of plasma 75Se-SELENOP, differentiating the brain from other tissues [10]. Interestingly, with the injection of 75Se-labeled SELENOP, the accumulation of 75Se in the Se-depleted rat brain two hours later was five-times greater (p < 0.05) than in Se-sufficient controls [11], while total body turnover for 75Se was insignificantly affected by Se status. Under low Se supply, the brain tends to store Se at a nearly constant level [12]. Se deprivation causes irreversible damage to neuronal tissue [12], [13]. Such hierarchy of Se homeostasis is good evidence for its essential functions in the brain [14] and SELENOP is thought to take a central part in maintaining such hierarchy [9]. Indeed, the impairment of brain Se homeostasis or severe Se deficiency causes highly detrimental neurological outcomes and can become lethal in extreme cases [4], [13]. Se seems to be involved in most molecular mechanisms related to neurodegeneration pathology and specifically in Alzheimer's disease (AD); these include redox pathways, myelopathies, signal transduction and cytoskeleton assembly [15], [16].

SELENOP is a potentially multifunctional protein with both enzymatic and Se-transport activities that plays a central role in body Se transport and maintaining tissue Se hierarchy [17]. Plasma/serum SELENOP concentration is therefore considered to be a more accurate biomarker of Se status than total serum Se or plasma/serum glutathione peroxidase (GPX3) activity [18], [19]. SELENOP plays an import role in the transport of Se to the brain for the synthesis of essential selenoproteins [16] such as GPX and thioredoxin reductase (TrxR) [20]. Currently, SELENOP is considered to be an indicator selenoprotein for the saturation of Se nutritional requirements [8], [21]. However, SELENOP functions are not limited solely to Se transport [19]; it contains a redox motif and exhibits certain antioxidant properties [12], [22] contributing to redox regulation. Experiments with transgenic mice showed that decreasing brain Se by genetic inactivation of SELENOP, or its receptor, apolipoprotein E-receptor type II (ApoER2) [23], [24], caused spontaneous neurological impairment and degeneration. AD is closely associated with protein misfolding [25], [26], leading to the formation of molecules that cause neuronal cell damage and synaptic dysfunction. Oxidative stress is an important molecular mechanism implicated in AD and other neurodegenerative conditions [27], [28], [29], hence the selenoproteins are potentially capable of counteracting AD development, owing to their antioxidant properties.

There is an age-associated increase in gene expression of SELENOP [30] which may indicate an increased demand for Se in the ageing organism. Moreover, in AD [31] and other neurodegenerative states [32], the SELENOP gene appears to be up-regulated even more. This fact and the neurological phenotype of Selenop-knockout animals implicate SELENOP in cognition and, in particular, give it a possible role in AD. Interestingly, in the brain, SELENOP uses the same receptor as apolipoprotein E (ApoE); ApoE polymorphisms are considered to be the strongest genetic risk factor for AD [33], [34]. The current review focuses on the recent findings that suggest the involvement of SELENOP in AD pathology, based on model and human studies. Although mainly positive aspects of SELENOP are featured in this review, we also comment on the detrimental effects of excessive Se supplementation or exposure, including potential neurotoxicity, elevated risk of type II diabetes mellitus (T2DM), certain malignancies and amyotrophic lateral sclerosis (ALS) [35], [36], with T2DM having SELENOP as a candidate protein that mediates impaired insulin response [37], [38], [39].

Section snippets

Biochemistry and functions of SELENOP

SELENOP is a secreted heparin-binding glycoprotein [40], mainly supplied to the blood by hepatocytes [12], [41], [42]. SELENOP is also present in extra-hepatic tissues, most notably in the brain [43] and testes [24]. Although SELENOP is a secreted protein, its intracellular presence was reported for neurons [43], testicular Leydig cells [44], adipocytes [45], and pancreatic β-cells [46]. SELENOP is the most abundant selenoprotein [47] in cerebrospinal fluid (CSF) which has been shown to have a

SELENOP interaction with bioactive components involved in Alzheimer's disease pathology

SELENOP, as a chemically active protein, containing multiple Sec and cysteine residues, interacts with a number of substances that may be related to brain pathology. First of all, its metal-binding capacities are widely known [92], [93]. Importantly, amyloid-β (Aβ) also has a strong affinity for metals, binding redox-active essential metals like Cu [94], [95], [96], [97], [98] and Fe [97] as well as Zn [91], [96], [97], [99], [100], which may alter Cu and Fe binding by protein homeostasis [7],

In vivo and ex vivo studies

Most of the evidence implicating SELENOP in neurodegeneration pathology and etiology is based upon murine transgenic studies. Selenop is one of three murine selenoprotein genes, which along with GPX4 and selenoprotein W (SELENOW), has a high level of expression in over 90% of murine brain regions, including the olfactory area, hippocampus, isocortex, and cerebellar cortex [108]. Interestingly, GPX4, the only GPX form required for proper embryogenesis [82], was recently reported to require Se,

Human studies linking Se exposure or supplementation to neurodegeneration

Since the central hypothesis that SELENOP has a role in AD and, more generally, in brain disorders, is linked to the delivery of Se to brain tissue for selenoprotein synthesis, we will examine the epidemiological evidence linking Se exposure/supplementation to neurodegeneration [6], [15], [34], [126], [127]. Observational epidemiological studies have shown that higher Se status benefits neurological function and cognitive performance. In the French EVA cohort of 1166 people aged 60–70 years

Potential mechanisms for the effect of SELENOP in Alzheimer's disease

The ApoE-ε4 allele is a well-known genetic risk factor for the late-onset sporadic AD in most populations [159]. The mechanism by which ApoE-ε4 increases the risk of AD is still to be characterized. For other alleles of ApoE, ApoE-ε3 and in particular ApoE-ε2, there is an enhanced proteolytic breakdown of Aβ, both intra- and extracellularly, so the increased vulnerability to the AD pathologic changes may be attributed to relative ineffectiveness of the ApoE-ε4 isoform to inhibit

Conclusion and perspectives

SELENOP, as a central selenoprotein underpinning body Se hierarchy and brain Se homeostasis, has an important role in the body. Research shows that SELENOP affects Aβ and hyperphosphorylated tau aggregation and toxicity in addition to interacting with redox-active metals in the brain, such as Cu, Fe, and Hg. It is capable of antioxidant enzyme activity and appears to possess signaling functions via neuronal ApoER2. As the Se-transport protein, it provides Se to neurons and glial cells to

Acknowledgements

We thank Dr. Marco Vinceti for valuable comments, which helped us to increase the quality of this paper. Nikolay Solovyev acknowledges the funding from the Russian Foundation for Basic Research (grant No. 16-33-60004 mol_a_dk). Yaroslav Dubrovskii thanks the St. Petersburg State University for personal funding.

Declaration of interest

None.

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      Citation Excerpt :

      Se has also been used as a therapeutic agent with contrasting results. Hence, Se has been discussed for decades in relation to AD, with absence of conclusive results [29]. It has been used as an adjunct to therapy in a multiple sclerosis mouse model, and has been proposed as preventive and therapeutic measures in distinct clinical forms of this disease [30].

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