硒对AD模型中金属离子内稳态和线粒体功能调控的机制研究

阿尔茨海默症（AD）是老年病中的第二“杀手”。金属离子内稳态紊乱和线粒体动力学及功能异常是AD发生的早期事件，直接影响Aβ聚集和tau磷酸化，最终导致不可逆的神经元损伤及AD发生。生物必需微量元素硒对维持中枢神经系统的正常功能具有重要作用。本项目拟在申请者前期工作基础上，从分子、细胞和动物三个层面，研究一种多功能（结合金属离子、调节氧化-还原平衡、调节脑内硒稳态）硒蛋白（SelP）和一种天然有机硒化合物（SMC）对AD的干预作用和分子机制。主要研究内容包括：1）SelP结合AD相关金属离子的热力学及动力学性质；2）SelP在体内调控金属离子内稳态的机制及对AD病理的干预作用；3）SMC通过纠正线粒体动力学和功能异常干预AD病理的机制；4）SMC通过调控金属离子内稳态干预AD病理的机制。本项目将首次研究硒对AD中金属离子内稳态和线粒体功能的调控机制，为将硒开发为AD防治药物提供基础数据。

Alzheimer’s disease (AD), the leading cause of dementia in elderly people, is now the most common neurodegenerative disease with no cure, affecting more than 46 million people worldwide. Dyshomeostasis of metal ions and dysfunction of mitochondria were happened in the very early stage of AD, which promoted Aβ aggregation, tau phosphoylation, and finally resulted in the irreversible synaptic loss and neuronal damage. As a vital trace element, selenium (Se) is essential for proper brain function and may be beneficial in reducing Alzheimer’s pathology. Selenoprotein P (SelP) plays important roles in regulating the cellular redox status, selenium and metal homeostasis due to the presence of the UXXC motif in the N-terminus, the Sec-rich domain in the C-terminus and the His-rich motifs in the middle part of the protein. Until now, studies on methyl-selenocysteine (SMC), a naturally occurring organoselenium compound found in many kinds of plant, are mainly focused on its anti-cancer or anti-oxidant activity, its potential in neurodegenerative disorders including AD has remained elusive. In this project, the potential roles of SelP and SMC in the intervention of AD as well as the underlying mechanisms will be explored at the molecular, cellular and organismal levels. Four Parts will be included in this project: 1) Kinetics and thermodynamics of metal binding to SelP; 2) Roles and the underlying mechanisms of SelP in the modulation of metal homeostasis and the implications in AD prevention; 3) Effects and mechanisms of SMC in maintaining the normal dynamics and function of mitochondria in AD; 4) Roles and the underlying mechanisms of SMC in the regulation of metal homeostasis and the implications in AD intervention. This project will study the effects and mechanisms of Se in the modulation of metal homeostasis and the dynamics and function of mitochondria in AD for the first time and will provide theoretical support and basic data for the development of new selenium-containing pre-drugs to prevent or combat AD.