本文關(guān)鍵詞： 帕金森病 MPTP 認(rèn)知障礙 帕金森病 MPTP tau蛋白 磷酸化　出處：《華中科技大學(xué)》2014年博士論文　論文類型：學(xué)位論文

【摘要】：第一部分MPTP亞急性及慢性損傷PD小鼠模型認(rèn)知障礙的研究 目的：探討MPTP亞急性損傷及慢性損傷PD小鼠模型的認(rèn)知改變。 方法：本研究分別用多次腹腔注射的MPTP亞急性損傷(25mg/kg*5天)和慢性損傷(25mg/kg*10次,3.5d/次)C57BL/6小鼠作為PD的動(dòng)物模型,等量生理鹽水腹腔注射作為對(duì)照,通過(guò)對(duì)多種神經(jīng)行為學(xué)指標(biāo)的動(dòng)態(tài)觀察,和認(rèn)知功能指標(biāo)的動(dòng)態(tài)觀察,探討各模型的運(yùn)動(dòng)障礙和認(rèn)知障礙,采用免疫組織化學(xué)方法了解MPTP導(dǎo)致的黑質(zhì)致密部酪氨酸輕化酶(TH)陽(yáng)性染色神經(jīng)元的變化。 結(jié)果：與對(duì)照組相比,亞急性損傷模型實(shí)驗(yàn)組小鼠爬桿試驗(yàn)和網(wǎng)格試驗(yàn)均異常,但是癥狀逐漸恢復(fù),3w、7w時(shí)和對(duì)照組相比無(wú)明顯意義；線索提示Morris水迷宮2w時(shí)潛伏期明顯延長(zhǎng),避暗實(shí)驗(yàn)4w時(shí)潛伏期有明顯延長(zhǎng),并持續(xù)存在；免疫組化顯示,小鼠中腦黑質(zhì)TH陽(yáng)性細(xì)胞數(shù)下降,隨時(shí)間延長(zhǎng)逐漸恢復(fù),2w時(shí)損傷小于50%。 與對(duì)照組相比,慢性損傷模型實(shí)驗(yàn)組小鼠爬桿試驗(yàn)和網(wǎng)格試驗(yàn)均異常,持續(xù)至7w時(shí)；線索提示Morris水迷宮2w時(shí)潛伏期明顯延長(zhǎng),避暗實(shí)驗(yàn)4w時(shí)潛伏期明顯延長(zhǎng),并持續(xù)存在；免疫組化顯示,小鼠中腦黑質(zhì)TH陽(yáng)性細(xì)胞數(shù)下降,隨時(shí)間延長(zhǎng)逐漸恢復(fù),8w時(shí)損傷依然大于50%。 結(jié)論：1、MPTP亞急性及慢性損傷PD小鼠模型,均出現(xiàn)運(yùn)動(dòng)障礙,亞急性模型運(yùn)動(dòng)障礙隨時(shí)間延長(zhǎng)恢復(fù),慢性模型持續(xù)時(shí)間更長(zhǎng),和TH陽(yáng)性細(xì)胞數(shù)變化一致。 2、MPTP亞急性及慢性損傷PD小鼠模型,均出現(xiàn)認(rèn)知障礙。 第二部分MPTP誘導(dǎo)的小鼠帕金森病認(rèn)知障礙模型中Tau蛋白磷酸化的變化 目的：觀察MPTP誘導(dǎo)的亞急性和慢性小鼠帕金森病認(rèn)知障礙模型中不同部位、不同時(shí)間Tau蛋白磷酸化的變化。 方法：采用western blot方法測(cè)定兩種模型中不同分組腦組織(紋狀體、黑質(zhì)、海馬、前額葉皮質(zhì))總tau蛋白和磷酸化tau蛋白的變化。 結(jié)果：在MPTP誘導(dǎo)的小鼠亞急性模型和慢性模型中,總tau蛋白水平?jīng)]有明顯變化,磷酸化tau (Ser262, Ser214, Ser396/404)蛋白的水平增加,Thr205位點(diǎn)tau蛋白磷酸化不明顯；造模后1W兩種模型中均是紋狀體磷酸化水平最高；亞急性模型實(shí)驗(yàn)組小鼠前額葉皮質(zhì)、海馬、紋狀體、黑質(zhì)磷酸化水平在1W或2W磷酸化水平達(dá)到最高,隨時(shí)間增加很快下降；慢性模型實(shí)驗(yàn)組黑質(zhì)在造模后第1W磷酸化水平增長(zhǎng)較少；紋狀體區(qū)第1W增長(zhǎng)較快,但是低于亞急性模型實(shí)驗(yàn)組；慢性模型實(shí)驗(yàn)組紋狀體、黑質(zhì)磷酸化水平在第1W或第2W達(dá)到最高水平；前額葉皮質(zhì)、海馬磷酸化水平緩慢增長(zhǎng),達(dá)到高峰時(shí)間晚于黑質(zhì)和紋狀體；總體磷酸化水平低于亞急性模型實(shí)驗(yàn)組,但是下降緩慢。 結(jié)論：MPTP誘導(dǎo)的亞急性和慢性小鼠帕金森病認(rèn)知障礙可能和磷酸化的tau蛋白有關(guān)。
[Abstract]:Part one: cognitive impairment in PD mice with subacute and chronic injury of MPTP. Objective: to investigate the cognitive changes of PD mice model with subacute and chronic injury of MPTP. Methods: in this study, MPTP subacute injury (25 mg / kg / kg for 5 days) and chronic injury (25 mg / kg / kg) were used as PD animal model, and normal saline was injected intraperitoneally as control. Based on the dynamic observation of various neurobehavioral indexes and cognitive function indexes, the motor and cognitive disorders of each model were discussed. Immunohistochemical method was used to investigate the changes of tyrosine light enzyme (THH) -positive neurons in the substantia nigra densification caused by MPTP. Results: compared with the control group, the Rod climbing test and grid test were abnormal in the subacute injury group, but there was no significant difference between the control group and the control group when the symptoms recovered gradually for 3 weeks, indicating that the latency of Morris water labyrinth was significantly prolonged at 2 weeks. The incubation period was significantly prolonged and continued to exist at 4 weeks after the dark avoidance test, and immunohistochemical staining showed that the number of th positive cells in the substantia nigra decreased, and the damage was less than 50 at 2 weeks after the gradual recovery of the cells in the substantia nigra of mice. Compared with the control group, the mice in the model group of chronic injury were abnormal in pole climbing test and grid test until 7 weeks, indicating that the latency of Morris water labyrinth was significantly prolonged at 2 weeks, and that of avoidance test was prolonged at 4 weeks. Immunohistochemical staining showed that the number of th positive cells in the substantia nigra decreased, and the damage was still greater than 50 at 8 weeks after recovery. Conclusion the subacute and chronic injuried PD mice models of MPTP have motor disorders. The motor disorders of subacute models recover with time, and the duration of chronic models is longer, which is consistent with the changes of th positive cells. 2 PD mice model with subacute and chronic injury of MPTP showed cognitive impairment. Part two changes of Tau protein phosphorylation in cognitive impairment model of Parkinson's disease in mice induced by MPTP. Aim: to observe the changes of Tau protein phosphorylation in subacute and chronic Parkinson's disease cognitive impairment models induced by MPTP. Methods: the changes of total tau protein and phosphorylated tau protein in different groups of brain tissues (striatum, substantia nigra, hippocampus, prefrontal cortex) were measured by western blot method. Results: in MPTP induced subacute model and chronic model, the level of total tau protein did not change significantly, but the level of phosphorylated tau ser262,214, Ser396 / 404) protein increased the phosphorylation of tau protein at Thr205 site. The phosphorylation level of prefrontal cortex, hippocampus, striatum and substantia nigra reached the highest at 1W or 2W in the subacute model group, and decreased rapidly with the increase of time. The level of phosphorylation in the substantia nigra of the chronic model group increased less at the 1st week after modeling, the first week in the striatum area increased more rapidly, but it was lower than that in the subacute model group, and the striatum of the chronic model experimental group increased more rapidly than the subacute model group. The level of phosphorylation in the substantia nigra reached its highest level at the first or second week, the phosphorylation level in the hippocampus of the prefrontal cortex increased slowly, reaching the peak time later than that of the substantia nigra and striatum, and the total phosphorylation level was lower than that in the subacute model group. But the decline is slow. Conclusion the cognitive impairment of subacute and chronic Parkinson's disease induced by 1: MPTP may be related to phosphorylated tau protein.
【學(xué)位授予單位】：華中科技大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R742.5

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9 田梅t，

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