本文選題：肝素寡糖 + β-淀粉樣蛋白　； 參考：《山東大學(xué)》2017年碩士論文

【摘要】：阿爾茲海默癥(Alzheimer's disease,AD)是一種進(jìn)行性發(fā)展的神經(jīng)功能障礙性疾病,老年人是其主要的發(fā)病人群。隨著人口老齡化情況加劇,阿爾茲海默癥已經(jīng)逐漸成為嚴(yán)重危害老年人健康的常見(jiàn)病。β-淀粉樣蛋白(β-amyloid peptide,Aβ)是AD病理性標(biāo)志淀粉樣斑塊的重要組成部分,tau蛋白是神經(jīng)元纖維纏結(jié)(neurofibrillarytangles,NFTs)的主要組成部分,而淀粉樣斑塊和NFTs是神經(jīng)病理學(xué)診斷AD的標(biāo)準(zhǔn)。但是,NFTs在很多神經(jīng)退行性疾病中觀(guān)察到,因此,β-淀粉樣蛋白成為研究AD的主要物質(zhì)。人類(lèi)終身產(chǎn)生Aβ,它是一種正常的生理代謝產(chǎn)物,其不正常的病理變化是引發(fā)AD的重要原因。研究發(fā)現(xiàn),糖胺聚糖(glycosaminoglycan,GAG)介導(dǎo)了Aβ的聚集并導(dǎo)致神經(jīng)毒性的發(fā)生,硫酸化的GAG能夠有效促進(jìn)Aβ的纖維化聚集,并且穩(wěn)定已形成的老年斑,但是未硫酸化的透明質(zhì)酸(hyaluronic acid,HA)不能夠促進(jìn)Aβ聚集。而肝素寡糖與Aβ結(jié)合可以有效的抑制Aβ的聚集并減少其神經(jīng)毒性。肝素寡糖不具有毒性且能夠通過(guò)血腦屏障(blood brain barrier,BBB)直接作用于Aβ。肝素寡糖混合物C3是一種低分子肝素(low molecular weight heparin,LMWH)衍生物,它是一種Aβ聚集抑制劑,已在臨床治療中應(yīng)用。然而該藥物是一種混合物,由于肝素可以與近百種蛋白質(zhì)相互作用并發(fā)揮不同的生理活性,混合物可能存在潛在的副作用,因此,需進(jìn)一步明確研究肝素寡糖與Aβ之間相互作用的構(gòu)效關(guān)系。本課題旨在研究不同硫酸化程度及硫酸化位點(diǎn)的肝素寡糖與Aβ之間的相互作用的差異性,從分子水平上研究明確結(jié)構(gòu)的寡糖與Aβ40結(jié)合的構(gòu)效關(guān)系。運(yùn)用質(zhì)譜(mass spectrum,MS)和核磁共振波譜(nuclear magnetic resonance,NMR)分析方法分別對(duì)制備的三種肝素四糖dp4-1、dp4-3、dp4-4和市售的磺達(dá)肝癸鈉(肝素五糖片段)進(jìn)行了結(jié)構(gòu)表征,確定了三種肝素四糖結(jié)構(gòu)分別為:ΔUA2S(1 →4)GlcNS6S(1 →4)IdoA2S(1 →4)GlcNS,ΔUA2S(1 →4)GlcNS6S(1 →4)GlcA(1→4)GlcNS6S,ΔUA2S(1→4)GlcNS6S(1→4)IdoA2S(1→4)GlcNS6S.五糖的結(jié)構(gòu)為GlcNS6S(1 →4)GlcA(1→4)GlcNS3S6S(1→4)IdoA2S(1→4)GlcNS6SOMe。利用凝膠遷移速率分析(gel mobility shift assay,GMSA)優(yōu)化寡糖與Aβ相互作用的最適條件,根據(jù)實(shí)驗(yàn)結(jié)果分析肝素四糖與Aβ相互作用強(qiáng)弱順序?yàn)?dp4-4dp4-1dp4-3。利用NMR分析方法研究寡糖與Aβ結(jié)合的明確位點(diǎn),結(jié)果表明肝素寡糖結(jié)構(gòu)中IdoA2S為必要的結(jié)合位點(diǎn),而GlcNS6S中的6S對(duì)兩者的相互作用起到增強(qiáng)的作用,而磺達(dá)肝癸鈉中具有特異性抗凝活性的3S結(jié)構(gòu)并未參與兩者相互作用。
[Abstract]:Alzheimer's disease (AD) is a progressive neurologic disorder in which the elderly are the main ones.As the population ages,Alzheimer's disease has gradually become a common disease that seriously endangers the health of the elderly. 尾 -amyloid peptide A 尾 is an important component of amyloid plaques in AD. Tau protein is the main component of neurofibrillary tanglesn (NFTs).Amyloid plaques and NFTs are the criteria for neurologic diagnosis of AD.However, NFTs have been observed in many neurodegenerative diseases. Therefore, 尾-amyloid protein has become the main substance in the study of AD.Human life produces A 尾, which is a normal physiological metabolite, and its abnormal pathological changes are the important causes of AD.It has been found that glycosaminoglycan (Gage) mediates the aggregation of A 尾 and leads to neurotoxicity. Sulfated GAG can effectively promote the accumulation of A 尾 fibrosis and stabilize the formation of senile plaques.But hyaluronic acid (HA), which was not sulfated, did not promote A 尾 aggregation.The binding of heparin oligosaccharide with A 尾 can effectively inhibit the aggregation of A 尾 and reduce its neurotoxicity.Heparin oligosaccharide is not toxic and can directly act on A 尾 through blood-brain barrier blood brain barrier.Heparin oligosaccharide mixture C3 is a low-molecular-weight heparin molecular weight weight LMWH.It is an A 尾 aggregation inhibitor and has been used in clinical treatment.However, the drug is a mixture, and because heparin can interact with nearly 100 proteins and perform different physiological activities, the mixture may have potential side effects, so,The structure-activity relationship between heparin oligosaccharide and A 尾 should be further studied.The purpose of this study was to study the difference of the interaction between heparin oligosaccharides and A 尾 at different sulfation levels and sites, and to study the structure-activity relationship between A 尾 40 and heparin oligosaccharides at molecular level.The structures of three kinds of heparin tetrasugar, dp4-1, dp4-3, dp4-4 and sulfodecyl sodium (heparin pentaccharide fragments), were characterized by mass mass spectrometry and nuclear magnetic resonance NMRs, respectively.Three types of heparin tetracosaccharide structures were identified as 螖 UA2S(1 4)GlcNS6S(1 4)IdoA2S(1 4GlcNS4GNC, 螖 UA2S(1 4)GlcNS6S(1 4)GlcNS6S(1 4)GlcA(1 4GlcNS6S, 螖 UA2S(1 4)GlcNS6S(1 4)IdoA2S(1 4GlcNS6S.The structure of pentaccharide is GlcNS6S(1 4)GlcA(1 4)GlcNS3S6S(1 4)IdoA2S(1 4 GlcNS6SOMe.The optimum conditions for the interaction of oligosaccharides with A 尾 were optimized by gel migration rate analysis. The order of the interaction between heparin tetrasugar and A 尾 was:: dp4-4dp4-1dp4-3.NMR analysis was used to study the specific site of oligosaccharide binding to A 尾. The results showed that IdoA2S was the necessary binding site in the structure of heparin oligosaccharide, while 6s in GlcNS6S enhanced the interaction between the two.However, the 3s structure with specific anticoagulant activity was not involved in the interaction.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R749.16;O657.2

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