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

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.

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。

硒缺乏是AD发生的高危因素，硒和硒蛋白在AD防治方面具有重要的潜力，但其具体作用机制尚不清楚。本项目主要完成了两大部分的研究内容。一是阐明了硒蛋白P(SelP)通过调控TrkB通路和锌离子内稳态干预AD病理的分子机制。采用腺病毒包装结合鼠脑定位注射，实现了SelP在AD模型小鼠海马及其辐射区域内的持续、大量表达。通过详细而深入地研究，发现：1）SelP显著改善AD模型小鼠的学习和记忆能力；2）抑制神经损伤和突触丢失；3）抑制tau病理及Aβ聚集；4）同时激活BDNF- 和 Src-介导的TrkB信号通路；5）通过增加MT3 和 ZnT3的表达，恢复了AD小鼠脑内的锌离子稳态。二是阐明了硒甲基硒代半胱氨酸（SMC）通过调控线粒体动力学和功能干预AD病理的分子机制，具体为：1）获得了SMC抗AD的最佳剂量与作用时间，为将SMC开发为AD防治药物前体或功能食品提供了重要的基础；2）发现SMC通过调控线粒体生物发生、能量代谢、分裂融合、线粒体膜保护、线粒体自噬等调控线粒体的结构与功能；3）此外通过蛋白质组学结合生物信息学研究发现，SMC逆转的蛋白主要涉及代谢、突触、抗氧化等，说明能量代谢障碍，突触功能失常和氧化应激可能是导致AD病理发生的重要事件，SMC通过调控上述事件干预了AD的发生发展。本项目首次完成了硒对AD模型中的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防治药物提供了重要的基础数据。