淀粉样蛋白和神经炎症复合调控剂的设计及作用机理

Alzheimer’s disease (AD) is a progressive neurodegenerative illness characterized by the decline of cognitive functions. Existing drugs can only relieve the symptoms but cannot terminate the course of disease. Therefore, the research of anti-AD drugs is of great importance in practice. The main pathological characteristics of AD are the deposits of β-amyloid protein (Aβ) formed in the cerebral cortex and outside of neural cells in the hippocampus area, the intracellular neurofibrillary tangles, and the activation of microglia and astrocyte cells that result in the neuron loss in the synapse. Since AD is a disease caused by multiple factors, multi-targeting drugs should be designed to deal with such pathogenesis. This project intends to combine the Aβ-targeting molecules with the anti-inflammation molecules, in order to synthesize a series of multifunctional molecules with some regulatory abilities for both Aβ aggregation and neuroinflammation. The structural characteristics of these compounds are the presence of two functional units, namely, an Aβ-targeting group and an anti-inflammatory group; also, a flexible metal-chelating setting is formed together by the coordination atoms in the targeting group, the linker and the anti-inflammatory group. The analogues of sulfur flavin T are chosen as the Aβ-targeting groups, and the analogues of non-steroidal anti-inflammatory drugs are selected as the anti-inflammatory groups. The project focuses on the effects of the combined molecules on regulating Aβ aggregation, pro-inflammatory factors and apoptotic proteins, as well as their therapeutic effects on nerve cells and model animals of AD.

阿尔茨海默病（AD）是以认知功能减退为特征的进行性神经变性疾病，现有药物只能缓解症状不能终止病程，所以研究抗AD药物具有重大的现实意义。AD的主要病理特征是大脑皮层和海马区神经细胞外以β-淀粉样蛋白（Aβ）沉积为核心形成的老年斑、细胞内神经原纤维缠结、小胶质细胞和星形胶质细胞激活以及由此导致的神经细胞突触减少。由于AD是多因素疾病，所以应该设计多靶点药物来应对。本项目拟将Aβ靶向分子与抗炎症分子并合，合成一系列对Aβ和神经炎症同时具有一定调节能力的复合多功能分子。该类化合物的结构特点为分子中含有两个功能单元，即Aβ靶向基团和抗炎症基团，此外还有一个柔性金属配位环境，由靶向基团、连接体和抗炎基团中的配位原子共同形成，其中Aβ靶向基团为硫黄素T类似物，抗炎基团为非甾体抗炎药类似物。项目将重点研究复合分子对Aβ聚集、各种促炎症因子和促凋亡蛋白的调节作用，并验证对神经细胞和AD模型动物的治疗效果。

阿尔茨海默病（AD）是以认知功能减退为特征的神经变性疾病，现有药物只能缓解症状不能终止病程，因此研究抗AD药物具有重要意义。AD的主要病理特征之一是大脑皮层和海马区神经细胞外形成的β-淀粉样蛋白（Aβ）沉积。神经炎症在AD发病机理中起重要作用，炎症因子、炎性小体、活性氧（ROS）、β-折叠构象等与AD有密切关系。锌、铜等金属离子能诱导Aβ形成β-折叠并快速沉积，产生高毒性ROS，对AD患者脑组织造成氧化损伤。本项目将Aβ靶向基团与非甾体抗炎药等药效基团偶联合成了一系列具有抑制Aβ聚集、神经炎症、炎性小体激活、β-折叠形成、或ROS产生等的多功能复合分子，并研究了它们对神经细胞和AD模型动物的治疗效果。其中双功能分子BIBA对Aβ自聚集和金属诱导的聚集具有显著的抑制作用，同时能减少小胶质细胞中的神经炎症，延长Aβ转基因秀丽隐杆线虫的寿命，减少AD模型鼠大脑中的Aβ斑块及神经炎症，具有改善AD症状的潜力。双功能分子BPBA除具有类似功能外，还能在体内外能抑制NLRP3炎性小体的激活并减少炎症因子的释放，减少Aβ寡聚物和斑块及ROS的形成，缓解神经毒性，阻止AD发展。多功能分子BPB能特异性识别不同的Aβ聚集体，定量血浆Aβ寡聚物中的β-折叠，还能解聚APP转基因小鼠脑浆中由金属离子诱导或自发的Aβ聚集体，抑制ROS产生，保护神经元免受Aβ毒性损伤，是潜在的AD诊断治疗剂。绿茶多酚EGC和ECG具有抗氧化性能，能螯合金属离子抑制Aβ聚集和ROS产生，特别是ECG能减少AD小鼠大脑中的Aβ斑块，保护神经元免受损伤，是预防AD的天然金属螯合剂及抗氧化剂。多金属氧酸盐CAM能特异性干预β-折叠形成，抑制金属诱导或自发的Aβ聚集和ROS产生，使神经元免受Aβ聚集物毒害，证明调节Aβ构象是预防AD的可行方法。总之，多功能复合调控剂利用协同作用抑制多重致病因素，为设计抗AD药物提供了新思路。