Different Effects and Mechanisms of Selenium Compounds in Improving Pathology in Alzheimer’s Disease

Abstract

Owing to the strong antioxidant capacity of selenium (Se) in vivo, a variety of Se compounds have been shown to have great potential for improving the main pathologies and cognitive impairment in Alzheimer’s disease (AD) models. However, the differences in the anti-AD effects and mechanisms of different Se compounds are still unclear. Theoretically, the absorption and metabolism of different forms of Se in the body vary, which directly determines the diversification of downstream regulatory pathways. In this study, low doses of Se-methylselenocysteine (SMC), selenomethionine (SeM), or sodium selenate (SeNa) were administered to triple transgenic AD (3× Tg-AD) mice for short time periods. AD pathology, activities of selenoenzymes, and metabolic profiles in the brain were studied to explore the similarities and differences in the anti-AD effects and mechanisms of the three Se compounds. We found that all of these Se compounds significantly increased Se levels and antioxidant capacity, regulated amino acid metabolism, and ameliorated synaptic deficits, thus improving the cognitive capacity of AD mice. Importantly, SMC preferentially increased the expression and activity of thioredoxin reductase and reduced tau phosphorylation by inhibiting glycogen synthase kinase-3 beta (GSK-3β) activity. Glutathione peroxidase 1 (GPx1), the selenoenzyme most affected by SeM, decreased amyloid beta production and improved mitochondrial function. SeNa improved methionine sulfoxide reductase B1 (MsrB1) expression, reflected in AD pathology as promoting the expression of synaptic proteins and restoring synaptic deficits. Herein, we reveal the differences and mechanisms by which different Se compounds improve multiple pathologies of AD and provide novel insights into the targeted administration of Se-containing drugs in the treatment of AD.

Sensorineural hearing loss and cognitive impairment: three hypotheses

“…Aβ is a peptide produced by hydrolysis of amyloid precursor protein (APP), and excess Aβ accumulation in mitochondria activates astrocytes and microglia, damages neurons ( Huang et al, 2023 ), and induces mitochondrial autophagy, promoting reactive oxygen species (ROS) production and accelerating neural oxidation ( Dou and Tan, 2023 ). At the same time, over-phosphorylation of tau protein eliminates its ability to form and maintain stable microtubules, reduces the dissociation of microtubule protein molecules, and induces microtubule bundling ( Kandimalla et al, 2018 ; Solas et al, 2023 ; Zhang et al, 2023 ). In turn, this affects neuronal cell signaling and the mitosis of other cell types in the brain.…”

Thioredoxin (Trx): A redox target and modulator of cellular senescence and aging-related diseases

“… [ 487 ] [ 377 ] [ 488 ] TrxR TrxR-interfering drug delivery system (based on RGD-PEG-PUSeSe-PEG-RGD self-assembling micelles)→TrxR→Cancer Se-methylselenocysteine (SMC)→TrxR→AD (NCT01497431, etc.) Butaselen (BS)→TrxR1→Hepatocellular carcinoma BBSKE (Ethaselen)→TrxR1→Cancer ACZ2→TrxR1→Gastric cancer Ethaselen→TrxR1→Lung cancer [ 360 ] [ 489 ] [ 490 ] [ 491 ] [ 492 ] [ 493 ] Michael receptor TrxR [ 6 ]-dehydroshogaol→TrxR→Cancer DVD-445 and its extended analogues→TrxR→Cancer [ 494 ] [ 495 ] Quinazoline derivatives TXNIP Quinazoline derivatives (D-2 & C-1)→TXNIP→Diabetes [ 496 ] Imidazole derivatives Trx1 PX-12 (1-methylpropyl 2-imidazolyl disulfide)→Trx1→Cancer [ 497 ] Benzopyrane derivatives Trx & TrxR SIMR1281→Trx & TrxR→Cancer [ 498 ] Other compounds and therapeutic methods Trx Ac-Cys-Pro-Cys-amide (thioredoxin-mimetic peptide)→Atherosclerosis Ascorbate & menadione→Trx→Cancer HSA-Trx→Trx→ND, PD, Cardiomyopathy PPa@GA/DSPE-PEG2K NPs→Trx→Cancer Au nanoclusters→...…”

Recent progress of nanomedicine in the treatment of Alzheimer’s disease

“…More importantly, Se can maintain neurotransmitters metabolizing at their normal rate, and as an antioxidant, Se can clear the brain of harmful substances. According to increasing evidence, Se NPs are promising nanoparticle carriers for inhibiting Aβ aggregation and decreasing Aβ neurotoxicity ( Zhang Z. H. et al, 2023 ). Se NPs have a particular affinity for Aβ, which causes Aβ deposition to decrease.…”