硒预防阿尔茨海默症中硒蛋白的新分子机制及关联性

A recent survey demonstrates that the population of elder people in China (> 60 years) will reach 438 million in 2050. Currently the prevalence of Alzheimer's disease (AD) is 1.6% in elderly, indicating that AD will be a huge problem in China in the future. The cause of AD occurs long before the obviously clinical symptom, and it grows in chain-reaction during the pathological process. Thus, it is very important to prevent the disease in its early stage. Deficiency of selenium, one of the biological trace elements, can result in the decrease of cognitive function. In our previous work, selenomethionine was found to significantly improve cognitive deficit, reduce the level of total tau and phosphorylated tau, mitigate the decrease of synaptic proteins in the hippocampus and cortex of the triple transgenic AD mice. Those results prompt us to systematically study the effect and mechanism of selenium in the prevention of AD. This project will use AD cell lines, primarily cultured neurons, and the triple transgenic AD mice as the study models. Various selenium-containing substances will be investigated for the efficiency in AD prevention at molecular, cellular, and animal levels, with the adoption of advanced methods currently used in our lab, such as the imaging of F-actin cytoskeleton and time-lapse imaging of mitochondria, methods of proteomics, genomics, and bioinformatics, and PET detection of alive mice brain. Meanwhile, new mechanisms of SelR and SelP involved in the pathological process of AD will also be studied, together with the coordination of TrxR and other selenoproteins in the intervention of AD with selenium. This project will provide theoretical support and basic data for the development of new selenium-containing anti-AD drug.

中国60岁以上老人预计到2050年达4.38亿，阿尔茨海默症（AD）患者目前在老人中占1.6%，提示AD可能将给中国社会带来巨大问题。AD发病过程长、呈链锁放大效应，尽早实施干预对预防和治疗AD至关重要。生物微量元素硒缺乏会造成认知功能降低。我们前期研究发现：硒代蛋氨酸能显著改善AD小鼠认知障碍、降低tau蛋白磷酸化、抑制神经突触蛋白减少，提示应对硒预防AD的效果和机制进行全面系统研究。本项目拟采用AD细胞系、原代神经细胞和三转基因AD小鼠，从分子、细胞、动物三个层面，结合实验室已具备的F-肌动蛋白细胞骨架成像和线粒体延时成像技术、各种组学研究手段和生物信息学方法、鼠脑PET活体检测手段，研究不同形态和剂量的含硒物质干预AD病理过程的效果，研究SelR和SelP对AD作用的新机制、多种硒蛋白经TrxR和Trx系统协同参与硒干预AD病理过程的机制。为开发抗AD含硒药物提供理论依据和基础数据。

阿尔茨海默症（AD）患者在60岁以上老人中占比1.6%，伴随人口老龄化，罹患AD将带来巨大社会问题。硒在脑中具有重要功能，缺硒造成认知功能降低。目前无有效AD治疗药物和早期诊断血液标志物。本项目基此开展研究，取得如下结果：（一）采用三转基因AD小鼠、原代培养神经细胞和AD细胞模型，研究了6种硒化合物干预AD的效果和机理。发现：1）硒酸钠能提高PP2A酶活性激活Wnt/β-catenin信号通路、抑制APP剪切形成Aβ；2）硒甲基硒代半胱氨酸（SMC）能抑制氧化应激和金属稳态失衡；3）伊布硒（Ebselen）能改善Aβ和tau病理指标；4）硒代蛋氨酸（Se-Met）能调控自噬通路、促进神经细胞再生；5）硒酵母通过长期膳食补硒逆转突触损伤、减轻tau病理变化。上述5种硒化合物因此显著改善AD小鼠认知障碍和病理指标。6）硒多糖（Se-PM）具有抗炎效应，是一种潜在的抗AD物质。（二）我们还研究了三种硒蛋白的调控机制，发现：1）硒蛋白R（SelR）通过多种途径调控Aβ聚集从而干预AD病理过程；2）硒蛋白W（SelW）通过与tau蛋白形成二硫键而诱导tau蛋白降解；3）硒蛋白F（SelF）通过与视黄醇脱氢酶11相互作用影响维生素A的代谢。基于上述研究成果，我们受邀参与了国际硒蛋白基因重新命名工作。（三）采用系统生物学研究方法我们发现：1）补充硒酸钠能显著逆转AD小鼠海马和皮层中靶蛋白表达水平及作用通路和网络的改变。2）补硒显著降低大多数金属离子在脑中的含量，尤其是铁离子，其含量被逆转恢复到正常水平，两种硒酶谷胱甘肽过氧化物酶（GPx）和硫氧还蛋白还原酶（TrxR）活性显著增加。3)补硒显著改善AD小鼠脑部葡萄糖代谢水平。4）从外周血中筛选出了一系列用于AD早期诊断的潜在标志物。上述研究成果为开发含硒抗AD新药提供了理论依据和基础数据。