本文選題：二苯乙烯苷 + 淀粉樣前體蛋白��； 參考：《首都醫(yī)科大學(xué)》2017年博士論文

【摘要】：第一部分:二苯乙烯苷對(duì)APP可變剪接的調(diào)節(jié)和干預(yù)作用目的:β淀粉樣蛋白(Aβ)聚集形成的老年斑是阿爾茨海默病(AD)的重要病理特征之一,由淀粉樣前體蛋白(APP)經(jīng)成淀粉途徑多次水解形成。人APP基因表達(dá)受可變剪接調(diào)控,人腦內(nèi)有三種APP可變剪接異構(gòu)體產(chǎn)物,分別是APP770,APP751和APP695。APP外顯子7編碼類似Kunitz蛋白酶抑制子功能的結(jié)構(gòu)域(Kunitz protease inhibitor domain,KPI),根據(jù)這些APP可變剪接異構(gòu)體是否表達(dá)外顯子7,可分為APP-KPI+和APP-KPI-兩種類型。據(jù)報(bào)道,APP-KPI+在腦內(nèi)的表達(dá)水平與Aβ的產(chǎn)生呈正相關(guān)。糖原合酶3β(Glycogen synthase kinase-3β(11)GSK3β)是腦內(nèi)和阿爾茨海默病(Alzheimer’s disease,AD)密切相關(guān)的重要激酶之一,它的活性在AD腦內(nèi)增加,是AD治療中的一個(gè)潛在的重要靶點(diǎn)。我們的前期研究發(fā)現(xiàn),何首烏主要成分二苯乙烯苷(tetrahydroxystilbene glucoside,TSG)能夠減少APP轉(zhuǎn)基因小鼠腦內(nèi)Ab含量和淀粉樣斑塊數(shù)量,改善學(xué)習(xí)記憶功能,但TSG對(duì)APP可變剪接和GSK3β的影響尚不清楚。本課題的目的是從分子、細(xì)胞和動(dòng)物整體水平系統(tǒng)研究GSK3β是否及如何通過(guò)磷酸化剪接因子從而調(diào)節(jié)APP外顯子7的可變剪接,探索AD早期病變機(jī)制,探討TSG對(duì)AD病理的影響,從而為臨床治療AD的新藥創(chuàng)制提供分子理論依據(jù)。方法:(1)構(gòu)建包含APP外顯子7、8可變剪接的微型基因(mini-gene)。設(shè)計(jì)針對(duì)外顯子6-9以及中間部分內(nèi)含子的各段引物,進(jìn)行PCR,然后將擴(kuò)增片段插入真核表達(dá)載體PCI-neo,轉(zhuǎn)染至HEK-293FT細(xì)胞系內(nèi)進(jìn)行剪接異構(gòu)體表達(dá)產(chǎn)物檢測(cè)。人胚胎腎細(xì)胞(HEK-293FT)、小鼠神經(jīng)母細(xì)胞瘤細(xì)胞(Neuro-2a,N2a)內(nèi)轉(zhuǎn)染APP mini-gene(包含了外顯子6-9,部分內(nèi)含子6、7、8)來(lái)模擬APP外顯子7、8在體內(nèi)的剪接。(2)在人神經(jīng)母細(xì)胞瘤細(xì)胞(SH-SY5Y)和N2a細(xì)胞系內(nèi)檢測(cè)APP微型基因的表達(dá)。針對(duì)APP770,APP751,APP695和總的APP設(shè)計(jì)特異的RT-PCR和熒光實(shí)時(shí)定量PCR(quantitative PCR,qPCR)引物,用普通PCR或熒光實(shí)時(shí)定量PCR(qPCR)測(cè)定APP各剪接異構(gòu)體或APP-KPI+的表達(dá)量。在N2a細(xì)胞內(nèi)過(guò)表達(dá)GSK3β或下調(diào)其表達(dá),用RT-PCR和qPCR觀察GSK3β對(duì)APP可變剪接的影響。(3)在HEK-293FT細(xì)胞內(nèi)共表達(dá)剪接因子ASF(alternative splicing factor)和激酶GSK3β,用HA抗體免疫共沉淀ASF,GSK3β抗體檢測(cè)ASF與GSK3β之間是否存在相互作用。此外,將HA-ASF、Myc-GSK3β轉(zhuǎn)染至HEK-293FT細(xì)胞,然后將ASF免疫沉淀,用磷酸化特異性抗體檢測(cè)免疫沉淀的ASF被磷酸化的程度。將ASF、GSK3β單獨(dú)或者共轉(zhuǎn)染至He La細(xì)胞中,用熒光二抗進(jìn)行染色,觀察ASF和GSK3β的細(xì)胞定位。(4)對(duì)SD(Sprague Dawley)大鼠進(jìn)行側(cè)腦室注射胰島素(Insulin),6小時(shí)后行RT-PCR和Western blot檢測(cè)各信號(hào)分子表達(dá)與活性,檢測(cè)PI3K-AKT通路,觀察APP-KPI+水平是否隨之變化。APP/PS1轉(zhuǎn)基因鼠TSG(50mg/kg/day)灌胃處理12個(gè)月,用Western blot或qPCR觀察鼠腦內(nèi)相關(guān)蛋白在m RNA和蛋白水平發(fā)生的改變。結(jié)果:(1)APP mini-gene在HEK-293FT和N2a細(xì)胞系內(nèi)進(jìn)行表達(dá),RT-PCR結(jié)果可見(jiàn)三個(gè)條帶,經(jīng)測(cè)序分別是APP770,APP751和APP695。其中APP-KPI+(770和751)表達(dá)量較之APP-KPI-(695)豐富,因此該微型基因是研究APP-KPI+的理想工具。過(guò)表達(dá)GSK-3β促進(jìn)APP微型基因產(chǎn)物APP-KPI+在N2a細(xì)胞內(nèi)的表達(dá),si GSK3β則抑制APP-KPI+表達(dá)量;不同濃度GSK3β抑制劑Li Cl處理SH-SY5Y細(xì)胞,內(nèi)源性APP-KPI表達(dá)量隨Li Cl濃度增高而降低。(2)各種剪接因子分別和APP微型基因共轉(zhuǎn)染HEK-293FT細(xì)胞,其中ASF對(duì)APP-KPI+的表達(dá)影響最大,是最為重要的APP可變剪接調(diào)控因子。GSK3β可以被ASF免疫共沉淀,存在生理上的相互作用,并且免疫共定位實(shí)驗(yàn)顯示ASF與GSK3β有很好的細(xì)胞內(nèi)共定位。激酶GSK3β可增加細(xì)胞內(nèi)剪接因子ASF絲氨酸磷酸化水平。然而,共表達(dá)ASF和GSK3β的細(xì)胞如果用TSG預(yù)處理48 h,ASF上絲氨酸磷酸化水平則下降。(3)TSG抑制HEK-293FT和SH-SY5Y細(xì)胞內(nèi)APP-KPI+的表達(dá)量,同時(shí)發(fā)現(xiàn)SH-SY5Y細(xì)胞內(nèi)源性AKT-GSK3β信號(hào)通路可被TSG激活,AKT和GSK3β的磷酸化水平顯著增加,呈現(xiàn)濃度依賴性,而AKT和GSK3β本身表達(dá)量無(wú)明顯變化。大鼠側(cè)腦室注射PI3K-AKT-GSK3β信號(hào)通路激活劑Insulin后6 h,檢測(cè)到AKT-GSK3β通路被激活。同時(shí),APP-KPI+的表達(dá)水平與對(duì)照組相比下調(diào)P0.05。(4)在體內(nèi)實(shí)驗(yàn)中,5月齡APP/PS1轉(zhuǎn)基因小鼠灌胃給藥TSG(50mg/kg/day)12個(gè)月后,腦內(nèi)AKT和GSK3β磷酸化水平增加,APP-KPI+表達(dá)水平降低。結(jié)論:本實(shí)驗(yàn)成功構(gòu)建了研究APP-KPI表達(dá)的微型基因。TSG可以激活神經(jīng)細(xì)胞和APP/PS1轉(zhuǎn)基因鼠腦內(nèi)的AKT-GSK3β通路;GSK3β可磷酸化剪接因子ASF,從而抑制其促進(jìn)APP-KPI+生成的能力;在體內(nèi)長(zhǎng)期喂食TSG可降低APP-KPI+表達(dá),從而預(yù)防Ab沉積。結(jié)果提示,TSG可能通過(guò)激活A(yù)KT-GSK3β信號(hào)通路而調(diào)節(jié)APP可變剪接,從而改善Ab病理變化。第二部分:EGCG對(duì)Dyrk1A調(diào)節(jié)APP可變剪接的影響目的:AD的病理特征之一是由Ab沉積形成的老年斑。本室前期研究發(fā)現(xiàn)雙特異性酪氨酸磷酸激酶1A(Dual specificity tyrosine-phosphorylation-regulated kinase1A,Dyrk1A)是腦內(nèi)重要的蛋白激酶,其活性在AD腦內(nèi)升高,同時(shí)Dyrk1A是一個(gè)潛在的基因可變剪接調(diào)節(jié)因子,已有的研究表明它介導(dǎo)了微管相關(guān)蛋白tau基因外顯子10的可變剪接調(diào)控,但尚未有報(bào)道Dyrk1A對(duì)APP可變剪接的研究。表沒(méi)食子兒茶素-3-沒(méi)食子酸酯(epigallocatechin-gallate,EGCG)屬綠茶天然提取物,毒性小。本研究的目的是研究Dyrk1A對(duì)APP微型基因和內(nèi)源性APP基因可變剪接的影響;通過(guò)細(xì)胞內(nèi)和整體動(dòng)物抑制Dyrk A活性,研究APP-KPI的表達(dá)變化和Ts65Dn模式小鼠的學(xué)習(xí)記憶行為學(xué)改變。方法:(1)轉(zhuǎn)染Dyrk1A真核表達(dá)質(zhì)�；驘o(wú)酶活性突變體(dominant negative)Dyrk1ADN至N2a細(xì)胞中,Real-time PCR檢測(cè)Dyrk1A對(duì)APP-KPI+表達(dá)量的影響。(2)培養(yǎng)SH-SY5Y細(xì)胞至密度80%左右,將不同劑量的Dyrk1A抑制劑駱駝蓬減(Harmine)加入到DMEM/F12基礎(chǔ)培養(yǎng)液中,24h后收取細(xì)胞提取細(xì)胞總RNA,用RT-PCR分析APP可變剪接變化。構(gòu)建APP770表達(dá)質(zhì)粒,轉(zhuǎn)染至HEK-293FT細(xì)胞,用Western blot檢測(cè)APP-KPI+表達(dá)改變,研究Dyrk1A抑制劑對(duì)APP-KPI+表達(dá)的影響。(3)抑制Dyrk1A活性對(duì)Ts65Dn模式鼠的行為學(xué)改變及分子生物學(xué)影響:從出生后即開(kāi)始給予小鼠含Dyrk1A抑制劑EGCG的飲食,2-3mg/day。喂食3個(gè)月后觀察喂藥組和對(duì)照組小鼠腦內(nèi)APP可變剪接的變化和學(xué)習(xí)記憶行為學(xué)改變。結(jié)果:(1)轉(zhuǎn)染Dyrk1A和無(wú)活性的Dyrk1A至N2a細(xì)胞,發(fā)現(xiàn)Dyrk1A明顯促進(jìn)APP-KPI表達(dá);而過(guò)表達(dá)無(wú)活性的Dyrk1A突變體,上述變化無(wú)顯著差異。(2)不同濃度Dyrk1A抑制劑Harmine作用于SH-SY5Y細(xì)胞,能夠抑制APP可變剪接,其表達(dá)產(chǎn)物APP-KPI+表達(dá)呈現(xiàn)Harmine濃度依賴性降低。(3)轉(zhuǎn)染Dyrk1A各種缺失突變體至SH-SY5Y細(xì)胞中,觀察到缺失C-端部分序列的Dyrk1A突變體與全長(zhǎng)相比,不同程度促進(jìn)APP-KPI表達(dá)。RT-PCR和Western blot統(tǒng)計(jì)分析結(jié)果均提示Dyrk1A的缺失突變體對(duì)APP可變剪接較之野生型影響更大。(4)行為學(xué)變化:Ts65Dn模式鼠和正常對(duì)照鼠相比,空間學(xué)習(xí)記憶能力顯著降低。EGCG能夠減低Ts65Dn小鼠腦內(nèi)APP-KPI+水平,同時(shí)受損的空間學(xué)習(xí)記憶能力有所改善。結(jié)論:Dyrk1A調(diào)節(jié)APP可變剪接,過(guò)表達(dá)Dyrk1A促進(jìn)APP-KPI+生成,抑制它的活性則APP-KPI+表達(dá)量降低。給予Ts65Dn模式鼠EGCG飲食能夠抑制Dyrk1A活性,降低腦內(nèi)APP-KPI表達(dá)量,改善學(xué)習(xí)記憶行為學(xué)變化。
[Abstract]:Part 1: two the regulation and intervention of two styrene glucoside on variable splicing: the accumulation of beta amyloid protein (A beta) is one of the important pathological features of Alzheimer's disease (AD), which is hydrolyzed by amyloid precursor protein (APP) through the starch pathway. Human APP gene expression is regulated by variable splicing and three in the human brain APP variable splice isomer products, APP770, APP751 and APP695.APP exon 7, encode the domain of the function of the Kunitz protease inhibitor (Kunitz protease inhibitor domain, KPI). According to whether these APP variable splice isomers express exon 7, they can be divided into two types: APP-KPI+ and two types. The expression level is positively related to the production of A beta. The glycogen synthase 3 beta (Glycogen synthase kinase-3 beta (11) GSK3 beta) is one of the important kinases closely related to the Alzheimer 's disease (AD) in the brain. Its activity is increased in the AD brain. It is a potential important target in AD treatment. Tetrahydroxystilbene glucoside (tetrahydroxystilbene glucoside, TSG) can reduce the Ab content and the number of amyloid plaques in the brain of APP transgenic mice and improve the learning and memory function. However, the effect of TSG on APP variable splicing and GSK3 beta is not clear. The purpose of this topic is to study the GSK3 beta from the molecular, cell and animal level system. And how to adjust the variable splicing of APP exon 7 by phosphorylated splicing factors, explore the early pathological mechanism of AD and explore the effect of TSG on the pathology of AD, thus providing molecular theoretical basis for the new drug creation of AD in clinical treatment. Method: (1) constructing a microgene (mini-gene) containing 7,8 variable splicing of the exon APP (mini-gene). A design needle of exon 6-9 is designed. PCR was carried out and the amplified fragment was inserted into the eukaryotic expression vector PCI-neo and transfected into the HEK-293FT cell line to detect the expression product of the splice isomer. The human embryonic renal cell (HEK-293FT) and the mouse neuroblastoma cells (Neuro-2a, N2a) transfected with APP mini-gene (including exon 6-9, Part 6-9, part). Intron 6,7,8) to simulate the splicing of APP exon 7,8 in the body. (2) the expression of APP microgenes in human neuroblastoma cells (SH-SY5Y) and N2a cell lines. Specific RT-PCR and fluorescent real-time quantitative PCR primers for APP770, APP751, APP695 and total APP are designed. CR (qPCR) measured the expression of APP splice isomers or APP-KPI+. The expression of GSK3 beta in N2a cells was overexpressed and the effect of GSK3 beta on APP variable splicing was observed with RT-PCR and qPCR. (3) co expression of splicing factor ASF and kinase inhibitor beta in HEK-293FT cells The interaction between ASF and GSK3 beta was detected. In addition, HA-ASF, Myc-GSK3 beta was transfected into HEK-293FT cells, ASF was then immunized, and phosphorylated specific antibodies were used to detect the degree of phosphorylation of ASF in the immunoprecipitation. ASF, GSK3 beta was separately or co transfected to He La fine cell, and the fluorescence two was stained to observe ASF and beta beta. (4) the SD (Sprague Dawley) rats were injected with insulin (Insulin) in the lateral ventricle. After 6 hours, RT-PCR and Western blot were used to detect the expression and activity of each signal molecule, and the PI3K-AKT pathway was detected, and the APP-KPI+ level was observed for 12 months in the TSG (50mg/kg/day) treatment of.APP/PS1 transgenic mice. The changes in the level of M RNA and protein in the rat brain were observed. Results: (1) APP mini-gene was expressed in HEK-293FT and N2a cell lines, and the results of RT-PCR showed three bands, which were APP770, APP751 and APP695. respectively. The expression of APP-KPI+ (770 and 751) was richer than that of APP-KPI- (695). Therefore, the microgene was studied. GSK-3 beta promoted the expression of APP microgene product APP-KPI+ in N2a cells, and Si GSK3 beta inhibited the expression of APP-KPI+; GSK3 beta inhibitor Li Cl treated SH-SY5Y cells at different concentrations, and the endogenous APP-KPI expression decreased with the increase of concentration. (2) all kinds of splicing factors were co transfected with miniature genes. Cells, in which ASF has the greatest influence on the expression of APP-KPI+, is the most important APP variable splicing regulator.GSK3 beta can be immunized by ASF, and there is a physiological interaction, and the immunocallocating experiment shows that ASF and GSK3 beta have good intracellular co localization. The kinase GSK3 beta can increase the intracellular splicing factor ASF serine phosphorylation However, if the cells that CO expressed ASF and GSK3 beta were pretreated with TSG for 48 h, the level of serine phosphorylation on ASF decreased. (3) TSG inhibited the expression of APP-KPI+ in HEK-293FT and SH-SY5Y cells, and found that the endogenous AKT-GSK3 beta signaling pathway of SH-SY5Y cells could be activated by TSG, and the level of phosphorylation was significantly increased. There was no significant change in the expression of AKT and GSK3 beta. The AKT-GSK3 beta pathway was activated after the injection of PI3K-AKT-GSK3 beta activator Insulin in the lateral ventricle of the rat. Meanwhile, the expression level of APP-KPI+ was reduced to P0.05. (4) compared with the control group (5 month old APP/PS1 transgenic mice were administered for TSG (50mg/kg/da) (50mg/kg/da). Y) 12 months later, the level of phosphorylation of AKT and GSK3 beta in the brain increased and the expression level of APP-KPI+ decreased. Conclusion: this experiment successfully constructed a microgene.TSG that studies APP-KPI expression can activate the AKT-GSK3 beta pathway in the brain of neural cells and APP/PS1 transgenic mice; GSK3 beta can phosphorylate factor ASF, thus inhibiting the ability to promote APP-KPI+ generation. Force; feeding TSG for a long time in the body can reduce APP-KPI+ expression and prevent Ab deposition. The results suggest that TSG may regulate the APP alterable splicing by activating the AKT-GSK3 beta signaling pathway, thus improving the pathological changes of Ab. The second part: the effect of EGCG on Dyrk1A regulated APP variable splicing: one of the pathological features of AD is the senile plaque formed by Ab deposition. The previous study found that 1A (Dual specificity tyrosine-phosphorylation-regulated kinase1A, Dyrk1A) is an important protein kinase in the brain, its activity is elevated in the AD brain and Dyrk1A is a potential gene variable splicing regulator, which has been shown to mediate microtubule related proteins. The variable splicing regulation of exon 10 of tau gene is regulated, but there has not been a report on the study of Dyrk1A's alterable splicing of APP. Epigallocatechin -3- gallate (epigallocatechin-gallate, EGCG) is a natural green tea extract with small toxicity. The purpose of this study was to study the effect of Dyrk1A on the variable splicing of APP microgenes and endogenous APP genes; Intracellular and whole animals inhibited Dyrk A activity, studied the expression changes of APP-KPI and the learning and memory behavior changes in Ts65Dn model mice. Methods: (1) transfection of Dyrk1A eukaryotic expression plasmid or non enzyme active mutant (dominant negative) Dyrk1ADN to N2a cells, Real-time PCR detected the effect of Dyrk1A on the expression amount. (2) culture The density of 5Y cells was about 80%, and the different doses of Dyrk1A inhibitor camel subtraction (Harmine) were added to the basic culture medium of DMEM/F12. After 24h, the total RNA was extracted from the cells, and the variable splicing of APP was analyzed by RT-PCR. The APP770 expression plasmid was constructed and transfected to HEK-293FT cells, and the expression of APP was changed by Western blot. The effect of preparation on the expression of APP-KPI+. (3) inhibition of Dyrk1A activity on behavioral changes and molecular biology in Ts65Dn model rats: the diet of Dyrk1A inhibitor EGCG in mice was given after birth. After 3 months of feeding, the changes of APP alterable splicing in the brain of the feeding and control mice and the changes of learning and memory behavior were observed. Results: (1) the transfection of Dyrk1A and inactive Dyrk1A to N2a cells showed that Dyrk1A significantly promoted APP-KPI expression, and there was no significant difference in the above changes. (2) the Dyrk1A inhibitor Harmine acted on SH-SY5Y cells in different concentrations, and could inhibit APP variable splicing, and the APP-KPI+ expression of the expression product presented Harmine concentration. The dependence was reduced. (3) the Dyrk1A mutants of the deletion of the Dyrk1A deletion mutants to the SH-SY5Y cells were observed to be compared with the total length of the missing C- terminal sequence. The statistical analysis of APP-KPI expression.RT-PCR and Western blot at different degrees suggested that the Dyrk1A missing mutants have greater influence on APP variable splicing than the wild type. (4) behavior Study changes: Ts65Dn model mice and normal control rats, spatial learning and memory ability significantly reduced the ability of.EGCG to reduce the level of APP-KPI+ in the brain of Ts65Dn mice, while the impaired spatial learning and memory ability improved. Conclusion: Dyrk1A regulates APP alterable splicing, Dyrk1A promotes APP-KPI+ production and inhibits its activity in APP-KPI+ expression. Reduction of Ts65Dn EGCG diet can inhibit Dyrk1A activity, decrease the expression of APP-KPI in brain, and improve learning and memory behavior changes.

【學(xué)位授予單位】：首都醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R96

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