纳米金、复合纳米金通过降解和清除Aβ治疗阿尔茨海默症的研究

发布时间：2018-05-23 13:46

本文选题：阿尔茨海默症 + β淀粉样蛋白　；参考：《暨南大学》2017年硕士论文

【摘要】：阿尔茨海默症(AD)是最常见的神经变性疾病,影响着10%65岁或以上的人。它剥夺了人们的记忆,生理功能和尊严,成为继心脏病,癌症和中风的第四大死亡原因。AD主要是由于淀粉样蛋白(Aβ)斑块和神经纤维缠结(Tau)在大脑特定位置的沉积,触发了脑组织的变性。研究发现,Aβ聚集体具有明显的神经毒性,比如Aβ能够介导线粒体功能障碍、氧化应激、炎症等的发生,引发神经元死亡,并最终导致痴呆。目前临床上治疗AD的药物大多只是起到了缓解作用,因此研发有效的靶向Aβ的药物,进而干预AD的发病机制,成为当今的研究热点,主要包括:减少Aβ的产生,抑制Aβ的聚集,促进Aβ的降解,加快Aβ的清除等。第一章:概述了AD的症状及其病理性特征,接着介绍了Aβ的形成途径及其介导的神经毒性。重点阐述了现有的抗AD药物的作用靶点、血脑屏障的作用及药物透过血脑屏障的方式、纳米材料治疗AD的研究进展。最后说明本课题的选题意义及目的。第二章:β淀粉样蛋白从它的可溶性单体到不溶性纤维的形态改变是阿尔茨海默病的主要病理特征。然而,大多数的Aβ抑制剂存在着弱的Aβ纤维解聚能力以及低的血脑屏障(BBB)透过率的问题,严重限制了AD药物的发展。因此,我们设计合成了钌配合物修饰的Pen多肽功能化的金纳米星(Ru@Pen@PEG-AuNS),双核钌配合物作为荧光探针对纳米粒子进行实时追踪。Ru@Pen@PEG-AuNS不仅可以有效的抑制Aβ聚集,并且由于其独特的近红外吸收性质,能够在近红外的照射下对已有的Aβ纤维具有明显的解聚作用。此外,这个新颖的体系表现出了高的生物相容性和血液相容性,同时其具有显著的透过BBB的能力,有效的增加了SH-SY5Y细胞对纳米颗粒的摄取,保护SH-SY5Y细胞免受Aβ诱导的损伤作用。这些表明Ru@Pen@PEG-AuNS可作为治疗AD的潜在药物。第三章:自噬在维持生物体内稳态,发育及抑制肿瘤等许多生物功能中发挥着重要的作用,其产生的自噬体能包裹异常聚集蛋白质和老化细胞器并最终与溶酶体融合成自噬溶酶体。自噬溶酶体途径是降解自身异常物质的主要途径,通过促进长寿命蛋白和衰老细胞器的清除,保证细胞内微环境的稳定。目前自噬功能障碍已被认为参与了AD的发病机制。因此,自噬的激活提供了清除细胞内Aβ和减缓Aβ诱导的神经毒性的潜在手段。在这项研究中,我们设计合成了槲皮素(Quercetin,Qu)修饰的聚山梨酸酯80(polysorbate 80,P-80)包裹的AuPd核壳结构。研究表明,Concave cubic Qu@P-80@AuPd具有良好的生物相容性及高的血脑屏障透过率。此外,Concave cubic Qu@P-80@AuPd相对于Concave cubic P-80@AuPd及Qu可以更有效的激活SH-SY5Y细胞的自噬,促进自噬体与溶酶体的融合,加速Aβ的清除,保护SH-SY5Y细胞免受Aβ诱导的细胞毒性损伤。综上,Concave cubic Qu@P-80@AuPd可以作为一种潜在的自噬诱导剂治疗AD。
[Abstract]:Blzheimer (AD) is the most common neurodegenerative disease that affects people aged 10%65 or above. It deprives people of memory, physiological function and dignity, and becomes the fourth leading cause of death in heart disease, cancer and stroke,.AD mainly due to the deposition of amyloid (A beta) patches and nerve fiber tangles (Tau) in a specific location of the brain. The study found that A beta aggregates have obvious neurotoxicity, such as A beta can mediate mitochondrial dysfunction, oxidative stress, inflammation and so on, cause neuronal death, and eventually lead to dementia. Currently, most of the drugs in the clinical treatment of AD are only remission, so effective target to A beta is developed. Drugs, which interfere with the pathogenesis of AD, have become a hot spot of research today, including reducing the production of A beta, inhibiting the aggregation of A beta, promoting the degradation of A beta and accelerating the clearance of A beta. In Chapter 1: the symptoms and pathological characteristics of AD are summarized. Then the formation pathway of A beta and its mediated neurotoxicity are introduced, and the existing anti AD is emphasized. The target of drug action, the role of the blood brain barrier and the way the drug permeates the blood brain barrier, the research progress of nano materials for the treatment of AD. Finally, the significance and purpose of this topic are explained. The second chapter: the morphological changes of beta amyloid from its soluble monomers to insoluble fibers are the main pathological features of Alzheimer's disease. Most of the A beta inhibitors have weak A beta fiber depolymerization and low blood brain barrier (BBB) transmittance, which seriously restricts the development of AD drugs. Therefore, we designed and synthesized the ruthenium complex modified Pen peptide functionalized gold nanoscale (Ru@Pen@PEG-AuNS), and the BIS nuclear ruthenium complex as a fluorescent probe for nanoparticles. The time tracking.Ru@Pen@PEG-AuNS can not only effectively inhibit the aggregation of A beta, but also have obvious depolymerization effect on the existing A beta fiber under near infrared radiation due to its unique near infrared absorption properties. In addition, this novel system shows high biocompatibility and blood compatibility, and it has a significant transmission of BB. The ability of B to effectively increase the uptake of nanoparticles by SH-SY5Y cells and protect SH-SY5Y cells from A beta induced damage. These indicate that Ru@Pen@PEG-AuNS can be used as a potential drug for the treatment of AD. The third chapter: autophagy plays an important role in maintaining homeostasis, developing and inhibiting many biological functions, such as tumor, and its production. Autophagic autophagy can encapsulate abnormal aggregation proteins and aging organelles and eventually melt the lysosomes into lysosomes. Autophagic lysosome pathway is the main way to degrade its own abnormal substances, which can ensure the stability of microenvironment in cells by promoting the removal of long life proteins and senescent organelles. Autophagic dysfunction has been considered to have been considered. The pathogenesis of AD is involved. Therefore, the activation of autophagy provides a potential means of removing intracellular A beta and slowing the neurotoxicity induced by A beta. In this study, we designed and synthesized Quercetin (Qu) modified polysorbate 80 (polysorbate 80, P-80) wrapped AuPd shell structure. The study shows Concave cubic Qu@P-80@AuP. D has good biocompatibility and high permeability of blood brain barrier. In addition, Concave cubic Qu@P-80@AuPd can activate autophagy of SH-SY5Y cells more effectively relative to Concave cubic P-80@AuPd and Qu, promote the fusion of autophagosomes and lysosomes, accelerate the clearance of A beta, protect SH-SY5Y cells from the cytotoxic damage induced by A beta. Oncave cubic Qu@P-80@AuPd can be used as a potential autophagy inducer in the treatment of AD..
【学位授予单位】：暨南大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R749.16;TB383.1

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