本文選題：阿爾茨海默癥 + 超聲聯(lián)合微泡　； 參考：《深圳大學(xué)》2017年碩士論文

【摘要】：阿爾茨海默癥(Alzheimer’s disease,AD)是常見(jiàn)的老年癡呆癥之一,是進(jìn)行性發(fā)展的致死性神經(jīng)退行性疾病。病人臨床表現(xiàn)為認(rèn)知和記憶功能不斷惡化,日常生活能力進(jìn)行性減退,伴有神經(jīng)精神癥狀和行為障礙。利用藥物治療AD需要面臨的首要問(wèn)題是中樞神經(jīng)系統(tǒng)內(nèi)存在的血腦屏障阻擋了大部分藥物進(jìn)入大腦。天然藥物人參皂苷Rd(ginsenoside Rd,Rd)具有良好的神經(jīng)細(xì)胞保護(hù)作用,但對(duì)于AD的治療也面臨血腦屏障的問(wèn)題。目前,低頻聚焦超聲聯(lián)合微泡的方法能夠短暫、有效、局部地開(kāi)放血腦屏障,為腦部藥物輸送和阿爾茨海默癥的治療開(kāi)辟了一個(gè)嶄新途徑�；诖�,本課題提出采用低頻聚焦超聲聯(lián)合微泡作為藥物輸送手段,探索人參皂苷Rd治療AD轉(zhuǎn)基因動(dòng)物模型對(duì)其行為學(xué)及海馬蛋白組學(xué)的影響。本研究工作采用8月齡的三轉(zhuǎn)基因(PS1M146V/APPSwe/TauP301L,3xTg-AD)小鼠為研究對(duì)象,每隔一天對(duì)不同分組的AD小鼠進(jìn)行治療并持續(xù)六周。治療結(jié)束后,從學(xué)習(xí)記憶能力、焦慮和抑郁行為的改善多個(gè)方面對(duì)治療組動(dòng)物行為學(xué)水平進(jìn)行評(píng)估:采用Morris水迷宮和電跳臺(tái)行為學(xué)檢測(cè)小鼠學(xué)習(xí)記憶能力;采用曠場(chǎng)實(shí)驗(yàn)和高架十字迷宮檢測(cè)小鼠焦慮程度;采用了懸尾實(shí)驗(yàn)檢測(cè)小鼠抑郁程度。行為學(xué)結(jié)果表明,與未治療的3xTg-AD小鼠相比,經(jīng)超聲微泡聯(lián)合Rd治療后的3xTg-AD小鼠的學(xué)習(xí)記憶能力有顯著提高,并減輕3xTg-AD小鼠的焦慮,但不能減輕小鼠的抑郁程度;單純超聲微泡與單純Rd治療也能一定程度地改善3xTg-AD小鼠的學(xué)習(xí)記憶能力,但不能減輕3xTg-AD小鼠的焦慮及抑郁程度。在此基礎(chǔ)上,采用熒光差異凝膠電泳(two-dimensional fluorescence difference gel electrophoresis,2D-DIGE)聯(lián)合質(zhì)譜技術(shù)篩選經(jīng)治療后的3xTg-AD小鼠海馬區(qū)差異表達(dá)蛋白,與未治療的3xTg-AD小鼠對(duì)比。發(fā)現(xiàn)這些差異蛋白中,記憶相關(guān)蛋白UCHL1在單純Rd和單純FUSMB治療后的3xTg-AD小鼠海馬組織中均表達(dá)顯著上調(diào)。此外,超聲微泡聯(lián)合Rd能改變UCHL1、PGAM1和SYN1蛋白表達(dá),而這三個(gè)蛋白可能是參與超聲微泡聯(lián)合Rd改善3xTg-AD小鼠記憶能力的關(guān)鍵分子。本論文的主要?jiǎng)?chuàng)新點(diǎn)主要有:一、對(duì)于具有神經(jīng)元保護(hù)功能的天然藥物人參皂苷Rd,采用低頻超聲聯(lián)合微泡輸送其入腦,探索對(duì)AD動(dòng)物的治療效果,目前尚無(wú)報(bào)道;二、本課題采用的3xTg-AD小鼠是目前唯一的能同時(shí)表現(xiàn)出β-淀粉樣蛋白沉積和Tau相關(guān)病理特征的最先進(jìn)的轉(zhuǎn)基因AD動(dòng)物模型,是本研究的一大特色;三、本課題采用了多方面的行為學(xué)水平評(píng)估:學(xué)習(xí)記憶、焦慮和抑郁水平的評(píng)估,能夠較全面地評(píng)估低頻超聲聯(lián)合微泡輸送人參皂苷Rd入腦這種方法對(duì)AD動(dòng)物的治療效果。
[Abstract]:Alzheimer's disease (AD) is one of the most common Alzheimer's disease and a fatal neurodegenerative disease. The clinical manifestations of the patients were the deterioration of cognitive and memory function, the progressive decline of daily living ability, and neuropsychiatric symptoms and behavioral disorders. The primary problem with drug therapy for AD is that the blood-brain barrier in the central nervous system prevents most drugs from entering the brain. Ginsenoside Rd(ginsenoside rdd) has a good neuroprotective effect, but the treatment of AD also faces the problem of blood-brain barrier. At present, the combination of low frequency focused ultrasound and microbubbles can open the blood-brain barrier briefly, effectively and locally, which opens a new way for drug delivery in brain and the treatment of Alzheimer's disease. Based on this, this paper proposed the use of low-frequency focused ultrasound combined with microbubbles as a means of drug delivery, to explore the effects of ginsenoside Rd on the behavior and hippocampal proteomics of AD transgenic animal model. In this study, 8-month-old three-transgenic PS1M146V / APPSwe/ TauP301Ln3xTg-ADmice were used to treat AD mice with different groups every other day for six weeks. After the treatment, the behavioral level of the treatment group was evaluated from the aspects of learning and memory ability, anxiety and depression behavior. The learning and memory ability of mice was measured by Morris water maze and electric jump table behavior. Open field test and elevated cross maze were used to test the anxiety degree of mice, and suspending tail test was used to detect the degree of depression in mice. The behavioral results showed that compared with untreated 3xTg-AD mice, the ability of learning and memory of 3xTg-AD mice treated with ultrasound microbubbles combined with Rd was significantly improved, and the anxiety of 3xTg-AD mice was alleviated, but the degree of depression was not alleviated. The treatment of ultrasound microbubbles and Rd could also improve the learning and memory ability of 3xTg-AD mice to some extent, but could not alleviate the anxiety and depression of 3xTg-AD mice. On this basis, two-dimensional fluorescence difference gel electrophoresis2D-DIGE and mass spectrometry were used to screen differentially expressed proteins in hippocampal area of 3xTg-AD mice after treatment, and the results were compared with those of untreated 3xTg-AD mice. It was found that the expression of memory-associated protein (UCHL1) was significantly up-regulated in hippocampus of 3xTg-AD mice treated with Rd and FUSMB alone. In addition, ultrasound microbubbles combined with Rd can change the expression of UCHL1PGAM1 and SYN1 proteins, which may be the key molecules involved in the improvement of memory ability of 3xTg-AD mice by ultrasound microbubbles combined with Rd. The main innovations of this thesis are as follows: first, for the natural drug ginsenoside Rdwhich has neuron protection function, it is transported into the brain by low-frequency ultrasound combined with microbubble to explore the therapeutic effect of AD animal. The 3xTg-AD mice used in this study are the only advanced transgenic AD animal model which can display 尾 -amyloid deposition and Tau related pathological characteristics at present, which is one of the major characteristics of this study. In this study, we used a variety of behavioral assessment: learning and memory, anxiety and depression, which can comprehensively evaluate the therapeutic effect of low-frequency ultrasound combined with microbubble transport of ginsenoside Rd into the brain for AD animals.
【學(xué)位授予單位】：深圳大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R749.16

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