双功能螯合剂对金属诱导的β-淀粉样多肽聚集的抑制研究

Alzheimer's disease (AD) is a neurodegenerative disease. With growing population age in the world, the morbility of AD increases gradually, which causes a great threat to human health and the society development. One of the main characteristics of AD is the deposition of aggregated amyloid-β (Aβ) peptides in the brain tissue. The investigation has indicated that meta ions (e.g., Cu(II) and Zn(II) ) dyshomeostasis and their aberrant interactions with Aβ are the critical factors for Aβ aggregation and neurotoxicity, finally the AD progression。Therefore, modulating metal-Aβ interaction is an effective method to inhibit the Aβ aggregation and depress the neurotoxicity. This provides a theoretical basis for the treatment of AD with the metal chelating agent. In order to overcome the poor targeting and low blood-brain barrier (BBB) permeability of traditional chelators, this project would design and synthetise the bifunctional chelators with the specifically target ability to Aβ and the ability of chelating metals ions. These bifunctional chelators will be used to modulate metal-induced Aβ events such as aggregation and neurotoxicity. The chelators with the neuroprotection against neurotoxicity caused by metal induced Aβ aggregation would be investigated in vitro and in vivo from two aspects of the prevention and treatment of AD, and the related mechanism would be discussed. The comprehensive effect of the design of these chelators would be evaluated. The relationship between bioactivity and the molecular structure of these chelators would be revealed. The action mechanism of the chelators for prevention and treatment of AD would be clarified. These would lay the solid foundation for the design, screen, evaluation and development of anti-AD drugs.

阿尔茨海默症(AD)是一种神经退行性疾病，随着世界人口的老龄化，AD发病率不断升高，严重威胁着人类的健康和社会的发展。AD的一个主要病理学特征是脑部β淀粉样多肽(Aβ)聚集沉积，研究发现铜锌等金属离子的代谢失衡以及金属-Aβ异常相互作用是引发Aβ聚集和神经毒性最终导致AD发生的关键因素，这为以金属螯合剂为手段治疗AD提供了理论依据。本项目针对传统螯合剂靶向特异性差、血脑屏障通透性低等局限性，在充分认识金属-Aβ相互作用机理的基础上，拟设计、合成既具有Aβ靶向识别能力又具有金属螯合能力的双功能螯合剂，通过体外体内实验，从预防和治疗AD两方面研究螯合剂对金属诱导Aβ聚集导致神经毒性的保护作用并探讨相关机制，评价螯合剂设计的综合效果，揭示螯合剂生物活性与分子结构的关系，阐明金属螯合剂防治AD的作用机理，为抗AD药物的设计、筛选、评价和开发奠定坚实的基础。

阿尔茨海默(AD)是一种神经退行性疾病，其症状主要表现为记忆、语言表达和逻辑推理等功能的衰退和丧失，在老龄人口中发病率很高，目前在世界上是仅次于心脏病、癌症和中风的第四位导致死亡的疾病。随着人口老龄化程度的加剧，AD患者逐渐增加，给社会和家庭带来了沉重的负担。对AD病的研究和治疗已成为人们关注的焦点，目前应用于AD病治疗的药物多是一些改善和缓解症状类药物，很难从根本上治愈。因此，制定“治本性”的防治策略和开展靶向性药物研发，已成为亟待解决的一项重大课题。AD的主要病理学特征是老年斑(SP)和神经纤维缠结(NFT)，老年斑的主要成分是β-淀粉样蛋白(Aβ)。研究发现铜锌等金属离子的代谢失衡以及金属–Aβ异常相互作用是引发Aβ聚集和神经毒性最终导致AD发生的关键因素，这为以金属螯合剂为手段治疗AD提供了理论依据。在本项目研究过程中，我们选择7个金属螯合剂，首先研究螯合剂对金属诱导Aβ聚集的调控性能，从分子水平上初步评价螯合剂的效果，探讨螯合剂防治AD的作用机理。其次，研究螯合剂对金属诱导Aβ聚集导致神经毒性的保护作用及机制，从细胞水平上进一步评价螯合剂的效果。最后，观察螯合剂对AD转基因小鼠脑组织Aβ聚集的影响，从整体动物水平了解螯合剂对AD病理学特征的影响，从三个方面来综合评价金属螯合剂效果。研究结果表明：这些金属螯合剂能够有效抑制Zn2+或Cu2+诱导的Aβ的聚集；能使得Zn2+或Cu2+诱导的Aβ的β-折叠构象基本逆转回起始的无规则卷曲构象；可以抑制Zn2+/Cu2+-Aβ的细胞毒活性，提高细胞存活率，缓解Cu2+-Aβ引起的细胞凋亡，降低细胞内的ROS水平。此外，选取了效果较好的表儿茶素没食子酸酯，对APPswe/PSEN1dE9转基因小鼠灌胃给药，通过刚果红染色来观察给药后转基因小鼠大脑皮层和海马区 Aβ斑块的变化，发现ECG可减少转基因小鼠脑内老年斑的生成，减缓AD进程。研究结果表明，这些金属螯合剂可以作为治疗AD潜在的神经保护剂和可能的候选药物。该项目研究阐明金属螯合剂防治AD的作用机理，为抗AD药物的设计、筛选、评价和开发奠定坚实的基础。