本文選題：阿爾茨海默病 + APP/PS1小鼠�。� 參考：《浙江大學(xué)》2016年博士論文

【摘要】：阿爾茨海默病(Alzheimer's disease, AD)是老年期癡呆最常見的病因,主要特點(diǎn)是進(jìn)行性的認(rèn)知和行為功能的損害。盡管全世界很多科學(xué)家都在致力于研究AD的病因,發(fā)病機(jī)制以及治療方法,但目前仍然沒有有效的可以治療或者使疾病停止惡化的藥物。有研究發(fā)現(xiàn)AD腦內(nèi)存在胰島素信號(hào)通路的缺陷,AD病人腦中胰島素受體(insulin receptor, IR)的表達(dá)和結(jié)合能力都有異常。而且用淀粉樣蛋白(amyloid beta, Aβ)寡聚體可以通過降低神經(jīng)元表面的IR或與胰島素競(jìng)爭(zhēng)受體的方式阻斷胰島素信號(hào)通路向細(xì)胞內(nèi)的傳遞。目前認(rèn)為AD的胰島素信號(hào)通路缺陷可能與散發(fā)性AD的發(fā)生相關(guān)。小范圍的臨床試驗(yàn)表明經(jīng)鼻吸入胰島素不僅可以改善健康受試者的注意力和記憶水平,對(duì)輕度認(rèn)知障礙(mild cognitive impairment,MCI)和AD病人的記憶也有改善作用。但是胰島素究竟是如何在AD病人的腦中發(fā)揮作用從而改善認(rèn)知功能的分子機(jī)制目前仍然不清楚。我們前期的研究發(fā)現(xiàn),對(duì)9月齡的三轉(zhuǎn)基因AD小鼠(3xTg-AD mice)經(jīng)鼻吸入胰島素治療1周后,可以修復(fù)胰島素信號(hào)通路的缺陷,增加腦內(nèi)突觸蛋白的水平,降低腦內(nèi)Aβ40的含量,減少腦內(nèi)小膠質(zhì)細(xì)胞的激活。為了更進(jìn)一步地研究經(jīng)鼻吸入胰島素對(duì)早期AD病理改變的影響,我們采用4.5月齡的APP/PS1雙轉(zhuǎn)基因AD小鼠模型(APPswe/PS1dE9, APP/PS1),經(jīng)鼻吸入胰島素1U/天給藥6周后,對(duì)AD模型小鼠的基本生理狀況,行為學(xué),分子生物學(xué)等進(jìn)行了一系列的探索,主要的研究方法和結(jié)果如下：1.我們將所有的小鼠分成三組：APP/PS1胰島素組(APP/PS1-ins), APP/PS1生理鹽水組(APP/PS1-veh)和野生型生理鹽水組(WT-veh)。給藥前和給藥后每周對(duì)這些小鼠監(jiān)測(cè)體重,發(fā)現(xiàn)給胰島素組與給生理鹽水對(duì)照組以及非轉(zhuǎn)基因小鼠相比體重的變化無明顯差異。2.連續(xù)給藥6周后,為評(píng)估三組小鼠的焦慮狀態(tài)以及認(rèn)知功能的情況,我們做了曠場(chǎng)實(shí)驗(yàn)(Open Field, OF)和水迷宮測(cè)試(Morris Water Maze, MWM). APP/PS1小鼠與WT小鼠比焦慮水平增高,經(jīng)鼻吸入胰島素后能降低該組小鼠的焦慮狀態(tài)到WT小鼠的水平；在MWM實(shí)驗(yàn)的獲得性訓(xùn)練(Acquisition Phase)階段,三組小鼠的逃避潛伏期(Escape latency)和從入水點(diǎn)到平臺(tái)的游泳距離(Path length to platform)無顯著差異；在探查測(cè)驗(yàn)階段,各組小鼠在原來平臺(tái)所在象限所花的時(shí)間百分比也沒有顯著差別,這些結(jié)果表明6月齡的APP/PS1小鼠的窖認(rèn)知功能在水迷宮測(cè)試中還未表現(xiàn)出明顯的損害。但在反向迷宮實(shí)驗(yàn)(Reverse Morris Water Maze, rMWM)中,APP/PS1-veh小鼠的逃避潛伏期和游泳距離都比野生小鼠升高,胰島素給藥后有改善,提示APP/PS1小鼠已經(jīng)表現(xiàn)出了記憶行為的可塑性異常,胰島素對(duì)此有一定改善作用。3.免疫印跡方法分析三組小鼠的海馬組織中胰島素信號(hào)通路相關(guān)蛋白的表達(dá)水平,APP/PS1小鼠海馬胰島素信號(hào)通路相關(guān)蛋白的表達(dá)異常,經(jīng)鼻吸入胰島素可以改善這些蛋白表達(dá)的異常。與此結(jié)果相對(duì)應(yīng),c-Jun N-terminal kinase (JNK),這個(gè)在胰島素抵抗和AD的病理學(xué)中發(fā)揮重要作用的激酶在APP/PS1小鼠海馬中表達(dá)升高,經(jīng)鼻吸入胰島素降低JNK蛋白的磷酸化水平。4.免疫組化分析APP/PS1小鼠腦內(nèi)的淀粉樣蛋白斑塊(Amyloid βplaque, Aβ plaque)的沉積,APP/PS1腦內(nèi)存在明顯的斑塊沉積,統(tǒng)計(jì)分析提示經(jīng)鼻吸入胰島素可以減少APP/PS1小鼠皮層和海馬的淀粉樣斑塊數(shù)量和面積。斑點(diǎn)印記(Dotblotting)實(shí)驗(yàn)發(fā)現(xiàn)經(jīng)鼻吸入胰島素減輕APP/PS1小鼠海馬可溶性Ap寡聚體的含量。酶聯(lián)免疫吸附測(cè)定(enzyme linked immunosorbent assay, ELISA)結(jié)果顯示胰島素可以降低APP/PS1小鼠海馬可溶性Aβ40 and Aβ42的水平。5.為了進(jìn)一步研究胰島素是否影響蛋白淀粉樣前體蛋白(Amyloid precursor protein, APP)的剪切或影響APP蛋白的磷酸化從而使Ap的量發(fā)生變化,我們對(duì)APP蛋白的磷酸化水平以及APP加工過程中的中間產(chǎn)物做了免疫印跡分析。統(tǒng)計(jì)分析表明經(jīng)鼻吸入胰島素增加海馬sAPPα的含量,減少sAPPβ的含量,并且使CTFβ/CTFα的比例下降,但不影響APP磷酸化蛋白的水平。6.APP的剪切和Ap的代謝過程中有許多酶的參與,包括p位點(diǎn)APP剪切酶1(Beta-secretase 1, BACE 1),主要的α位點(diǎn)剪切酶ADAM10,以及與Ap的降解和清除有關(guān)的IDE, APOE和LRP1等,APP/PS1小鼠海馬BACE1和APOE水平與野生型小鼠相比升高,經(jīng)鼻吸入胰島素降低BACE1和APOE的表達(dá)水平,升高ADAM10的表達(dá),但對(duì)IDE和LRP1沒有明顯影響。7. APP/PS1小鼠腦內(nèi)星型膠質(zhì)細(xì)胞和小膠質(zhì)細(xì)胞的標(biāo)志蛋白表達(dá)均增加,但沒有發(fā)現(xiàn)胰島素對(duì)此有明顯的改善作用。與突觸相關(guān)的三個(gè)蛋白突觸前蛋白Synaptophysin,突觸后密度蛋白95 PSD-95,神經(jīng)突觸素1Synapsin 1在三組小鼠腦中的表達(dá)水平無顯著差異。8.6月齡APP/PS1小鼠海馬Tau蛋白,磷酸化Tau蛋白的水平無明顯異常；對(duì)與Tau磷酸化相關(guān)的幾個(gè)激酶的免疫印跡分析也沒有發(fā)現(xiàn)表達(dá)水平的異常。9.胰島素增加APP/PS1小鼠海馬內(nèi)主要的神經(jīng)元發(fā)生標(biāo)志蛋白doublecortin的水平。終上所述,6月齡的APP/PS1轉(zhuǎn)基因小鼠在水迷宮實(shí)驗(yàn)中雖然未表現(xiàn)出明顯的認(rèn)知功能障礙,但在反向迷宮測(cè)試中已經(jīng)表現(xiàn)出了記憶可塑性的損害,經(jīng)鼻吸入胰島素對(duì)此有改善作用。APP/PS1小鼠焦慮水平升高,吸入胰島素可緩解小鼠的焦慮水平。對(duì)小鼠海馬的生化分析顯示APP/PS1小鼠腦內(nèi)胰島素信號(hào)通路存在異常,胰島素部分改善該信號(hào)通路的異常,可能與胰島素能減輕小鼠腦內(nèi)的JNK蛋白激活有關(guān)。轉(zhuǎn)基因小鼠海馬可溶性的Aβ40和A肛2水平,可溶性Ap寡聚體的含量,以及腦內(nèi)淀粉樣斑塊的沉積均表現(xiàn)出不同程度的升高。吸入胰島素后改善了腦內(nèi)的Ap病理變化。進(jìn)一步的研究發(fā)現(xiàn)胰島素可能是通過調(diào)節(jié)APP蛋白的剪切加工,使APP蛋白的剪切更多地朝著不產(chǎn)生Ap的途徑進(jìn)行,并恢復(fù)腦內(nèi)升高的APOE蛋白水平來減輕Ap病理變化。經(jīng)鼻吸入胰島素還對(duì)腦內(nèi)神經(jīng)元的發(fā)生有促進(jìn)作用。
[Abstract]:Alzheimer's disease (AD) is the most common cause of Alzheimer's disease, characterized by progressive cognitive and behavioral impairment. Although many scientists around the world are devoted to the study of the etiology, pathogenesis and treatment of AD, there is still no effective treatment or cessation of the disease. Studies have found that the AD brain is deficient in the insulin signaling pathway, and the expression and binding ability of the insulin receptor (insulin receptor, IR) in the brain of AD patients is abnormal. And the amyloid (amyloid beta, A beta) oligomer can block the islets by reducing the IR on the surface of the neuron or by the insulin competition receptor. It is believed that the deficiency of AD's insulin signaling pathway may be associated with the occurrence of sporadic AD. Small range of clinical trials suggest that inhaled intranasal insulin can not only improve the level of attention and memory of healthy subjects, but also the memory of mild cognitive impairment (mild cognitive impairment, MCI) and AD patients. However, it is still unclear how insulin plays a role in the brain of AD patients and improves the molecular mechanism of cognitive function. Our previous study found that 9 month old of the three transgenic AD mice (3xTg-AD mice) could repair the defects of the insulin signaling pathway after 1 weeks of nasal inhalation of insulin. Increase the level of synapse protein in the brain, reduce the content of A beta 40 in the brain and reduce the activation of microglia in the brain. In order to further study the effect of nasal inhalation of insulin on the early pathological changes of AD, we used the 4.5 month old APP/PS1 double transgenic mouse model (APPswe/ PS1dE9, APP/PS1), and administered the nasal inhalation insulin for 6 weeks at 1U/ days. After that, a series of studies were carried out on the basic physiological status, behaviourology and molecular biology of AD model mice. The main methods and results were as follows: 1. we divided all the mice into three groups: APP/PS1 insulin group (APP/PS1-ins), APP/PS1 saline group (APP /PS1-veh) and wild type saline group (WT-veh). The weight of the mice was monitored every week, and there was no significant difference in weight between the insulin group and the normal saline control group and the non transgenic mice. After 6 weeks of.2. continuous administration, we made an open field experiment (Open Field, OF) and water maze test (Morri) to evaluate the anxiety state and cognitive function of the mice (Morri S Water Maze, MWM). The anxiety level of APP/PS1 mice and WT mice was higher than that of WT mice. After inhalation of insulin, the mice could reduce the anxiety state of the mice to the level of WT mice; the escape latency (Escape latency) and the swimming distance from the water entry point to the platform of the three groups in the MWM experiment acquired training (Acquisition Phase) stage. There was no significant difference in GTH to platform, and there was no significant difference in the percentage of time spent in the quadrant of the original platform at the exploratory test stage. These results showed that the cellar cognitive function of the 6 month old APP/PS1 mice did not show obvious damage in the water maze test. But in the reverse labyrinth test (Reverse Morris Water M) In aze, rMWM), the escape latency and swimming distance of APP/PS1-veh mice were higher than those in the wild mice, and the insulin was improved after the administration of insulin, suggesting that the APP/PS1 mice had shown the malfunction of the memory behavior, and the insulin was improved by the.3. immunoblotting method to analyze the insulin signaling pathway in the hippocampus of the three groups of mice. The expression level of related proteins, the abnormal expression of insulin signaling pathway related proteins in the hippocampus of APP/PS1 mice, can improve the abnormal expression of these proteins through the nasal inhalation of insulin. Corresponding to this result, c-Jun N-terminal kinase (JNK), a kinase that plays an important role in the insulin resistance and AD pathology, is in the APP/PS1 mice sea. The expression in the horse was elevated and the JNK protein phosphorylation level was reduced by the nasal inhalation of insulin.4. immunohistochemical analysis of the amyloid plaques (Amyloid beta plaque, A beta plaque) in the brain of APP/PS1 mice. The APP/PS1 brain was deposited in the distinct plaque. Statistical analysis suggested that the inhalation of insulin through the nose could reduce the cortex and hippocampus of APP/PS1 mice. The number and area of the amyloid plaque. The Dotblotting experiment found that the nasal inhalation of insulin alleviated the content of soluble Ap oligomers in the hippocampus of APP/PS1 mice. The results of enzyme linked immunosorbent assay (enzyme linked immunosorbent assay, ELISA) showed that insulin could lower the level of soluble A beta 40 and A beta 42 in the hippocampus of APP/PS1 mice. 5. in order to further study whether insulin affects the shear of protein amyloid precursor protein (Amyloid precursor protein, APP) or affects the phosphorylation of APP protein to change the amount of Ap, we have made an immunoblotting analysis of the phosphorylation level of the APP protein and the intermediate products in APP processing. Insulin content increased the content of sAPP alpha in the hippocampus, reduced the content of sAPP beta, and reduced the proportion of CTF beta /CTF alpha, but did not affect the shear of the APP phosphorylated protein level.6.APP and the participation of many enzymes during the metabolic process of Ap, including the APP shear enzyme 1 (Beta-secretase 1, BACE 1) at the P site, the main alpha site shear enzyme ADAM10, and the p Degradation and scavenging related IDE, APOE and LRP1, BACE1 and APOE levels in the hippocampus of APP/PS1 mice were higher than that of wild type mice. Nasal inhalation of insulin reduced the expression of BACE1 and APOE, increased the expression of ADAM10, but did not significantly affect the marker proteins of astrocytes and microglia in IDE and LRP1. The expression was increased, but it was not found that insulin had a significant improvement. Three synaptosomal precursor protein Synaptophysin, postsynaptic density protein 95 PSD-95, and synaptophysin 1Synapsin 1 in the three group of mice had no significant difference in the.8.6 month old APP/PS1 mice hippocampus Tau protein, the phosphorylated Tau protein. There was no obvious abnormality in the level; the immunoblotting analysis of several kinases associated with Tau phosphorylation also showed no expression level of abnormal.9. insulin that increased the level of the major neuronal marker protein Doublecortin in the hippocampus of APP/PS1 mice. Finally, 6 month old of the APP/PS1 transgenic mice were not shown in the water maze experiment. There is obvious cognitive impairment, but the impairment of memory plasticity has been shown in the reverse labyrinth test. The inhalation of insulin by nasal inhalation improves the anxiety level of.APP/PS1 mice, and inhaled insulin can relieve the anxiety level of mice. Biochemical analysis of the hippocampus of mice shows the insulin signaling pathway in the brain of APP/PS1 mice. The abnormal insulin partially improves the signal pathway, which may be related to the ability of insulin to reduce the activation of JNK protein in the brain of mice. The content of soluble A beta 40 and A anus, the content of soluble Ap oligomers, and the deposition of amyloid plaques in the brain are all elevated in different degrees. Ap pathological changes in the brain are good. Further studies have found that insulin may be by modulating the shearing process of APP protein to make APP protein cut more towards the non Ap pathway, and to restore the level of APOE protein in the brain to alleviate the pathological changes of Ap. Use.

【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R749.16

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