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

Abstract

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.

Keywords: Alzheimer’s disease; Ca2+ homeostasis; brain function; neurotransmission; selenoprotein.

FIGURE 1

Ranking of the mRNA expression levels of 25 selenoproteins in the human brain. The fragments per kilobase of exon model per million mapped reads (FPKM) values of 25 selenoproteins in the brain obtained from gene transcriptome data were analyzed to rank selenoproteins based on their expression level in the human brain. The data are from the literature (Fagerberg et al., 2014).

FIGURE 2

Heat map of the distribution of 24 selenoproteins in the mouse brain. Based on genome-wide in situ hybridization data published in the ABA for the brains of adult mice, raw expression values of 23 selenoproteins in 12 regions in the mouse brain were analyzed and used to plot a heat map. The database contains no expression data for SELENOH in brain regions.

FIGURE 3

The effects of selenoproteins on the pathological processes of AD. (A,B) SELENOP, SELENOW and SELENOM inhibit the aggregation of Aβ and tau. SELENOS participates in the pathological protein degradation process through ERAD. (C) SELENOK affects the distribution of synaptic receptors. (D) GPX4 regulates ferroptosis-mediated neuronal apoptosis.