【摘要】：目的：觀察梓醇對(duì)APP/PS1雙轉(zhuǎn)基因阿爾茨海默病(Alzheimer'sDisease, AD)模型鼠空間學(xué)習(xí)記憶能力和自主活動(dòng)的影響以及腦內(nèi)老年斑的產(chǎn)生、神經(jīng)元丟失等典型病理特征的影響，并探討梓醇發(fā)揮作用的相關(guān)機(jī)制，為AD的防治提供新的思路。 方法：將3月齡的APP/PS1雙轉(zhuǎn)基因小鼠按照隨機(jī)數(shù)字表法隨機(jī)分為梓醇治療組和生理鹽水對(duì)照組，每組20只，并以10只同月齡的具有相同遺傳背景的C57小鼠作為正常對(duì)照，用梓醇(每天5mg/kg)和等量生理鹽水腹腔注射AD模型小鼠3周，應(yīng)用Morris水迷宮、曠場(chǎng)實(shí)驗(yàn)和高架十字迷宮(elevated plus maze, EPM)檢測(cè)小鼠空間學(xué)習(xí)記憶能力、自主活動(dòng)和焦慮情緒的變化；應(yīng)用免疫組織化學(xué)檢測(cè)各組小鼠腦內(nèi)老年斑與神經(jīng)元數(shù)量等的變化；通過Western blot檢測(cè)梓醇對(duì)小鼠腦內(nèi)β分泌酶活性及血管內(nèi)皮生長(zhǎng)因子(VEGF)等的影響。 結(jié)果：(1)行為學(xué)結(jié)果顯示：①在Morris水迷宮實(shí)驗(yàn)中，3組小鼠在可視平臺(tái)中找到平臺(tái)的平均潛伏期和搜索的平均路徑無明顯差異(P0.05)；隱蔽平臺(tái)實(shí)驗(yàn)中，梓醇治療組小鼠找到平臺(tái)的平均時(shí)間與搜索的平均距離較生理鹽水對(duì)照組小鼠明顯縮短(P0.01)，與正常對(duì)照組比較，無明顯差異(P0.05)；在探索實(shí)驗(yàn)中，60s內(nèi)梓醇治療組小鼠穿越平臺(tái)次數(shù)明顯高于生理鹽水對(duì)照組(P0.01)；②在曠場(chǎng)實(shí)驗(yàn)中，，梓醇治療組小鼠在中央?yún)^(qū)域停留的時(shí)間和路程顯著低于生理鹽水對(duì)照組(P0.01)；③在高架十字迷宮實(shí)驗(yàn)中，3組小鼠在總的穿臂次數(shù)和時(shí)間上沒有顯著差別(P0.05)，梓醇治療組小鼠穿越開臂的次數(shù)和停留在開臂上的時(shí)間要顯著的高于生理鹽水對(duì)照組(P0.01)，而與正常對(duì)照組相比，無顯著差異(P0.05)。(2)形態(tài)學(xué)檢測(cè)結(jié)果：免疫組化的結(jié)果分析顯示，與生理鹽水對(duì)照組相比，梓醇對(duì)照組小鼠大腦皮質(zhì)和海馬區(qū)域老年斑數(shù)量明顯減少(P0.01)，神經(jīng)元、神經(jīng)元前體細(xì)胞以及血管數(shù)量明顯增多，凋亡細(xì)胞顯著減少。(3)蛋白水平測(cè)定結(jié)果：Western blot結(jié)果顯示，與生理鹽水對(duì)照組相比，梓醇治療組小鼠腦組織中APP全蛋白的表達(dá)無明顯變化，BACE1的表達(dá)顯著減少(P0.01)，同時(shí)突觸相關(guān)蛋白PSD95蛋白與血管內(nèi)皮生長(zhǎng)因子(VEGF)的表達(dá)顯著增多(P0.01)。 結(jié)論：梓醇可顯著提高APP/PS1雙轉(zhuǎn)基因小鼠的空間學(xué)習(xí)記憶能力，緩解其焦慮情緒與自主活動(dòng)；梓醇可顯著減少APP/PS1雙轉(zhuǎn)基因小鼠腦內(nèi)Aβ的沉積與老年斑的數(shù)量，可能是通過抑制APP代謝過程中BACE1的活性，加強(qiáng)血管的對(duì)Aβ清除來實(shí)現(xiàn)的；梓醇通過抑制神經(jīng)細(xì)胞的凋亡，同時(shí)促進(jìn)神經(jīng)元再生，減少了AD模型鼠腦內(nèi)神經(jīng)元與突觸的丟失
[Abstract]:Objective: to observe the effect of catalpol on spatial learning and memory ability and autonomic activity in APP/PS1 double transgenic Alzheimer's disease (Alzheimer'sDisease, AD) model mice, as well as the production of aging plaques and the loss of neurons in the brain. The related mechanism of catalpol was discussed to provide a new idea for the prevention and treatment of AD. Methods: three months old APP/PS1 double transgenic mice were randomly divided into catalpol treatment group (n = 20) and saline control group (n = 20), and 10 C57 mice with the same genetic background were used as normal control. AD model mice were intraperitoneally injected with catalpol (5mg/kg per day) and the same amount of saline for 3 weeks. Morris water maze, open field test and elevated cross maze (elevated plus maze, EPM) were used to detect the spatial learning and memory ability of mice. The changes of autonomous activity and anxiety; The changes of aging plaques and the number of neurons in the brain of mice in each group were detected by immunohistochemistry, and the effects of catalpol on 尾 secretase activity and vascular endothelial growth factor (VEGF) in the brain of mice were detected by Western blot. Results: (1) the results of behavior showed that: (1) in the Morris water maze test, there was no significant difference in the average latency of finding the platform and the average path of searching in the visual platform of the three groups (P 0.05). In the hidden platform experiment, the average time of finding the platform and the average distance of search in the catalpol treatment group were significantly shorter than those in the saline control group (P 0.01), but there was no significant difference between the catalpol treatment group and the normal control group (P 0.05). In the exploration experiment, the number of mice crossing the platform in the 60 s catalpol treatment group was significantly higher than that in the saline control group (P 0.01). (2) in the open field experiment, the stay time and distance in the central area of the catalpol treatment group were significantly lower than those of the saline control group (P 0.01). (3) in the elevated cross maze test, there was no significant difference in the total number and time of arm piercing among the three groups (P 0.05). The frequency of crossing the open arm and the time of staying on the open arm in the catalpol treatment group were significantly higher than those in the saline control group (P 0.01), but compared with the normal control group, There was no significant difference in morphology (P 0.05). (2). The results of Immunohistochemical analysis showed that the number of aged plaques in cerebral cortex and hippocampus of catalpol control group was significantly lower than that of saline control group (P01), and the number of aged plaques in cerebral cortex and hippocampus of catalpol control group was significantly lower than that of saline control group. The number of neurons, neuronal progenitor cells and blood vessels increased significantly, while apoptotic cells decreased significantly. (3): Western blot results showed that compared with saline control group, the results of protein level assay showed that the number of neurons, neuronal progenitor cells and blood vessels was significantly increased and apoptotic cells were significantly decreased. In catalpol treatment group, the expression of APP whole protein in brain tissue did not change significantly, but the expression of BACE1 decreased significantly (P01), while the expression of synaptic related protein PSD95 protein and vascular endothelial growth factor (VEGF) increased significantly (P01). Conclusion: catalpol can significantly improve the spatial learning and memory ability of APP/PS1 double transgenic mice and alleviate their anxiety and autonomous activity. Catalpol can significantly reduce the deposition of A 尾 and the number of aged plaques in the brain of APP/PS1 double transgenic mice, which may be realized by inhibiting the activity of BACE1 in the process of APP metabolism and strengthening the clearance of A 尾 by blood vessels. Catalpol reduces the loss of neurons and synapses in the brain of AD model mice by inhibiting the apoptosis of nerve cells and promoting the regeneration of neurons.
【學(xué)位授予單位】：重慶醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2013
【分類號(hào)】：R749.16

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