ABSTRACT
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.
Subject(s)
Alzheimer Disease/metabolism , Disease Models, Animal , Receptors, N-Methyl-D-Aspartate/metabolism , Selenium/metabolism , Selenoproteins/metabolism , Synapses/metabolism , Animals , Cells, Cultured , Female , Male , Mice , Mice, TransgenicABSTRACT
It is unclear whether regular exercise depletes body iron stores and how exercise regulates iron absorption. In this study, growing female Sprague-Dawley rats were fed a high-iron diet (300 mg iron/kg) and subjected to swimming for 1, 3, or 12 months. Their body weight, liver nonheme iron content (NHI), spleen NHI, blood hemoglobin (Hb) concentration, hematocrit (Hct), and kinetics of 59Fe transfer across isolated duodenal segments were then compared with sedentary controls. The main results were as follows: exercise for 1 month enhanced the transepithelial 59Fe transfer and increased liver NHI content and Hb concentration; exercise for 3 months inhibited transepithelial 59Fe transfer without affecting the liver and spleen NHI content, Hb concentration, and Hct; exercise for 12 months did not affect these parameters as compared with the corresponding sedentary controls; and the changes in transepithelial iron transfer were not associated with basolateral iron transfer. Our findings demonstrated that chronic, regular exercise in growing rats with a high dietary iron content does not deplete iron stores in the liver and spleen and may possibly enhance or inhibit duodenal iron absorption and even maintain duodenal iron absorption at the sedentary level, at least, in part depending on growth.