Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, Nuthetal 14558, Germany.
Department of Molecular Nutritional Physiology, Institute of Nutritional Sciences, Friedrich Schiller University Jena, Dornburger Str. 24, Jena 07743, Germany; TraceAge, DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly (FOR 2558), Potsdam, Jena, Berlin, Germany.
J Trace Elem Med Biol. 2023 Jul;78:127149. doi: 10.1016/j.jtemb.2023.127149. Epub 2023 Mar 12.
Both essential trace elements selenium (Se) and copper (Cu) play an important role in maintaining brain function. Homeostasis of Cu, which is tightly regulated under physiological conditions, seems to be disturbed in Alzheimer´s (AD) and Parkinson´s disease (PD) patients. Excess Cu promotes the formation of oxidative stress, which is thought to be a major cause for development and progression of neurological diseases (NDs). Most selenoproteins exhibit antioxidative properties and may counteract oxidative stress. However, expression of selenoproteins is altered under conditions of Se deficiency. Serum Se levels are decreased in AD and PD patients suggesting Se as an important factor in the development and progression of NDs. The aim of this study was to elucidate the interactions between Cu and Se in human brain cells particularly with respect to Se homeostasis.
Firstly, modulation of Se status by selenite or SeMet were assessed in human astrocytes and human differentiated neurons. Therefore, cellular total Se content, intra- and extracellular selenoprotein P (SELENOP) content, and glutathione peroxidase (GPX) activity were quantified. Secondly, to investigate the impact of Cu on these markers, cells were exposed to copper(II)sulphate (CuSO) for 48 h. In addition, putative protective effects of Se on Cu-induced toxicity, as measured by cell viability, DNA damage, and neurodegeneration were investigated.
Modulation of cellular Se status was strongly dependent on Se species. In detail, SeMet increased total cellular Se and SELENOP content, whereas selenite led to increased GPX activity and SELENOP excretion. Cu treatment resulted in 133-fold higher cellular Cu concentration with a concomitant decrease in Se content. Additionally, SELENOP excretion was suppressed in both cell lines, while GPX activity was diminished only in astrocytes. These effects of Cu could be partially prevented by the addition of Se depending on the cell line and Se species used. While Cu-induced oxidative DNA damage could not be prevented by addition of Se regardless of chemical species, SeMet protected against neurite network degeneration triggered by Cu.
Cu appears to negatively affect Se status in astrocytes and neurons. Especially with regard to an altered homeostasis of those trace elements during aging, this interaction is of high physiological relevance. Increasing Cu concentrations associated with decreased selenoprotein expression or functionality might be a promoting factor for the development of NDs.
必需微量元素硒（Se）和铜（Cu）在维持大脑功能方面都起着重要作用。在生理条件下，Cu 的稳态受到严格调节，但在阿尔茨海默病（AD）和帕金森病（PD）患者中似乎受到干扰。过量的 Cu 会促进氧化应激的形成，氧化应激被认为是神经退行性疾病（NDs）发展和进展的主要原因。大多数硒蛋白具有抗氧化特性，可对抗氧化应激。然而，在 Se 缺乏的情况下，硒蛋白的表达会发生改变。AD 和 PD 患者的血清 Se 水平降低，表明 Se 是 NDs 发展和进展的重要因素。本研究的目的是阐明人脑细胞中 Cu 与 Se 之间的相互作用，特别是关于 Se 稳态。
首先，通过亚硒酸钠或硒代蛋氨酸评估 Se 状态的调节在人星形胶质细胞和人分化神经元中。因此，量化了细胞总 Se 含量、细胞内外硒蛋白 P（SELENOP）含量和谷胱甘肽过氧化物酶（GPX）活性。其次，为了研究 Cu 对这些标志物的影响，将细胞暴露于硫酸铜（CuSO）48 小时。此外，还研究了 Se 对 Cu 诱导的毒性的潜在保护作用，如细胞活力、DNA 损伤和神经退行性变的测定。
细胞 Se 状态的调节强烈依赖于 Se 物种。具体而言，硒代蛋氨酸增加了细胞总 Se 和 SELENOP 含量，而亚硒酸钠则导致 GPX 活性和 SELENOP 排泄增加。Cu 处理导致细胞内 Cu 浓度增加 133 倍，同时 Se 含量降低。此外，两种细胞系的 SELENOP 排泄均受到抑制，而仅在星形胶质细胞中 GPX 活性降低。这些 Cu 的作用可以部分通过添加 Se 来预防，具体取决于细胞系和使用的 Se 物种。尽管添加 Se 并不能防止 Cu 诱导的氧化 DNA 损伤，但硒代蛋氨酸可防止 Cu 触发的神经突网络退化。
Cu 似乎会对星形胶质细胞和神经元中的 Se 状态产生负面影响。特别是在衰老过程中这些痕量元素的内稳态发生改变的情况下，这种相互作用具有很高的生理相关性。与降低的硒蛋白表达或功能相关的 Cu 浓度增加可能是 NDs 发展的促进因素。
