C-jun氨基末端激酶在大鼠脑缺血再灌注后tau蛋白异常高度磷酸化和神经细胞凋亡中的作用
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摘要
研究背景
随着社会发展和人类饮食结构的改变,脑血管病的发病率呈明显上升趋势,世界范围内脑卒中的发病率为150-200／10万人,其中缺血性脑卒中高达85%。在我国每年新发脑卒中约200万例,每年死于脑血管病约150万例。在神经外科也广泛存在脑缺血性损伤如：脑外伤后并发的缺血性脑损伤,颅内动脉瘤夹闭术中误夹载瘤动脉或术后血管痉挛造成的缺血性损伤以及术中控制性降压不当导致的脑缺血损伤等。缺血性脑卒中的血管阻塞导致的急性脑缺血需要迅速的血管再通,而脑血流的再灌注会导致脑组织缺血再灌注损伤。脑缺血再灌注损伤主要涉及神经细胞能量耗竭、兴奋性谷氨酸神经递质毒性、钙离子超载、迟发性细胞死亡、自由基损伤、各种细胞因子的释放、半暗带区的去极化以及炎症反应等。这些复杂的病理变化导致钙调节蛋白依赖性激酶(CaMKs)和有丝分裂原激活蛋白(MAPKs)信号转导通路：细胞外信号调节激酶(ERK),p38和c-Jun氨基末端激酶(JNK)的激活。
流行病学调查发现脑卒中明显增加了痴呆的发病率,这些痴呆患者的病情多呈进行性发展,而且一半以上患者发生的继发性痴呆不是脑卒中脑损害直接导致的。阿尔茨海默病(Alzheimer's Disease, AD)是一种退行性病变,它是引起老年痴呆的最常见病因,临床症状主要是进行性记忆力丧失和认知功能障碍,病理学上主要表现为神经纤维缠结形成以及皮质神经元的丢失和老年斑的生成。AD的病因至今不明,发现家族性AD存在多个基因位点的异常,而散发性AD的发病机制比较复杂可能与脑缺血再灌注损伤有关,脑缺血、缺氧和自由基损伤可能是AD发生的重要病因。脑卒中的血管危险因素可使AD的患病风险增高,增加脑供血改善脑灌注不足可以明显改善AD的临床症状,并且脑血管疾病和AD之间存在相似的神经病理学特征如：脑缺血和AD中都存在tau蛋白的高度异常磷酸化和神经元的凋亡。但脑缺血后是否发生了和AD一样神经病理学特征目前还不清楚。因此进一步证实脑缺血再灌注损伤后是否发生AD样病理变化对阐明脑缺血和AD之间的关系是很有意义的。
tau蛋白是一种在神经系统广泛表达的微管相关蛋白,具有稳定微管,促进微管装配、维持神经元的形态和促进轴突运输的重要作用。tau蛋白功能异常改变可能是神经元功能障碍和死亡的必要环节。tau蛋白的磷酸化和去磷酸化间平衡是维持微管稳定性的关键调控因素,tau蛋白的高度异常磷酸化是神经系统退行性病变如：AD、皮克病(Pick's disease)等的特征性病理变化。在AD中tau蛋白的过度异常磷酸化导致tau蛋白自身聚集成双螺旋纤维细丝(paired helical filament, PHF),进而产生具有阿尔茨海默病特征性病理改变-神经纤维缠结(neurofilament tangles, NFTs)。目前发现tau蛋白的磷酸化位点多达21个,主要的磷酸化位点是Thr231、Ser396、Ser404、Ser199、Ser202、Thr205、Ser262等。这些位点的过度磷酸化主要有蛋白激酶GSK-3β、cdk5和MAPK来调节的。
JNK/SAPK是MAPKs的一条重要信号转导通路之一,JNK是上世纪90年代早期发现的能被许多应激因子激活,且能使核转录因子c-Jun的氨基活化区磷酸化的丝氨酸／苏氨酸蛋白激酶。它在AD的发病机制中具有重要作用,目前发现其能磷酸化tau蛋白的位点主要有Thr205、Ser396、Ser422、Ser202、Ser404、Ser199、Thr212、Thr231。tau蛋白的异常磷酸化是AD病的早期事件,它被认为是NFTs形成的关键,并且其与AD中神经元的丢失有关。JNK信号转导通路在局灶性脑缺血再灌注损伤后被激活,但JNK在局灶性脑缺血后tau蛋白异常过度磷酸化中的作用目前还不清楚。
脑梗塞时血管支配的区域中心就会形成缺血核心区和周边的半影区,核心区以神经元坏死为主,半影区则以神经元凋亡为主。而缺血的半影区是神经元保护的关键点。在AD中凋亡相关基因bcl-2、bax的表达和高度磷酸化的tau蛋白阳性细胞存在相关关系,同样bcl-2、bax在脑缺血后的表达也发生变化。JNK是脑缺血再灌注损伤后神经细胞凋亡的主要调节因子,bax是JNK在脑缺血再灌注损伤后调节神经细胞凋亡的主要促凋亡基因,而脑缺血再灌注后又诱导了tau蛋白的异常高度磷酸化。因此我们推测脑缺血后神经细胞的凋亡可能与高度异常磷酸化的tau蛋白相关,它们可能与AD一样是通过调节相同的凋亡相关基因bcl-2、bax来实现的,脑缺血后JNK有可能导致tau蛋白的高度异常磷酸化引发细胞凋亡进而发生AD样病变值得探讨。
故本研究利用大鼠大脑中动脉栓塞模型研究脑缺血后在AD患者脑中具有特征性的tau蛋白异常过度磷酸化位点的磷酸化变化,磷酸化tau蛋白的溶解性以进一步阐明脑缺血和阿尔茨海默病的关系。并且研究JNK在脑缺血再灌注损伤后tau蛋白异常过度磷酸化和凋亡相关基因bcl-2、bax的表达之间的联系,以及脑缺血再灌注损伤后异常过度磷酸化的tau蛋白和bax的表达空间关系并检测阻断JNK的活性后对脑缺血再灌注后梗塞灶体积的影响,进一步阐明JNK在脑缺血损伤后tau蛋白磷酸化和神经细胞凋亡中的作用。
目的：应用改良的MCAO线栓法制作大鼠局灶性脑缺血再灌注模型,并评价该模型的效果、稳定性为后继实验奠定基础。方法：将3-0尼龙线插入CCA内,并不断调整栓塞线进入的角度使其顺利进入ICA,前端到达大脑前动脉的起始部,通过阻断大脑中动脉的血供而造成大脑中动脉供血区脑缺血,栓塞线进入深度约(20±3)mm。并应用TTC染色及神经功能学评分评估大鼠局灶性脑缺血再灌注模型的效果及稳定性。结果：造模成功者一般状况较差,TTC染色发现梗塞灶明显、稳定性好,变异较小。除少数动物造模死亡外,其余神经功能学评分都在1-3分之间。结论：改良的MCAO线栓模型创伤小；实验结果稳定、可重复性强,为脑缺血再灌注实验提供有力保障。
目的：探讨局灶性脑缺血再灌注后大鼠皮质神经元tau蛋白磷酸化的变化,以阐明脑梗死和阿尔茨海默病间的关系。方法：制作局灶性脑缺血再灌注模型,应用免疫印迹法检测局灶性脑缺血再灌注后大鼠顶叶皮质tau蛋白在Ser199/202、Ser396、Ser404和Thr231位点磷酸化和非溶性磷酸化tau蛋白的变化。结果：脑缺血再灌注6h后皮质tau蛋白在Serl99/202、Ser396、Ser404和Thr231位点发生异常高度磷酸化,非溶性磷酸化tau蛋白显著增加。结论：脑缺血再灌注后发生阿尔茨海默病样病理变化,脑梗死可能促进阿尔茨海默病的发生、发展。
目的：探讨JNK在局灶性脑缺血再灌注后大鼠皮质神经元的tau蛋白过度磷酸化和bcl-2、bax的表达中的作用,以及脑缺血再灌注损伤后异常过度磷酸化的tau蛋白和bax的空间关系并检测阻断JNK的活性后对脑缺血再灌注后梗塞灶体积的影响,进一步阐明JNK在脑缺血损伤后tau蛋白磷酸化和神经细胞凋亡中的作用。方法：制作局灶性脑缺血再灌注模型,应用免疫印迹检测JNK的活性变化以及应用其特异性阻断剂SP600125阻断JNK的活性后大鼠顶叶皮质tau蛋白在Ser396和Thr231、Ser199/202、Ser404位点磷酸化的变化；免疫荧光双标法分别检测脑缺血再灌注后bax的表达和磷酸化tau蛋白的关系,应用TTC法检测SP600125对梗塞灶体积的影响。结果：脑缺血再灌注损伤后JNK的活性增加,应用SP600125阻断JNK的活性后显著抑制脑缺血再灌注后tau蛋白在Ser396和Thr231、Serl99/202、Ser404位点的磷酸化和促凋亡蛋白bax的表达,并且明显减小梗塞灶的体积。脑缺血再灌注后bax的表达与tau蛋白高度磷酸化存在显著相关性。结论：JNK在脑缺血再灌注后阿尔茨海默病样病理变化中起了重要作用,其可作为脑缺血再灌注后痴呆的一个治疗靶点。
Research Background
Along with the social development and the changing of human dietary structure, the prevalence of cerebral vascular disease has increased gradually. The worldwide incidence of stroke is 150-200/100,000, up to 85% of which is ischemic. There are about 2 million cases of new-onset stroke in our country annually, and 1.5 million domestic patients die of CVD every year. Cerebral ischemic injury are also found extensively in the neurosurgical practice, such as brain trauma complicated with cerebral ischemia, vasospasm after the aneurysm incarcerated operation and wrongly clipping of the parent artery or inappropriate controlled hypotension during the operation. The acute ischemia usually suggests a timely repatency, which can aggravate the ischemia in return.
The mechanism of cerebral ischemic/reperfusive injury is mainly associated with the energy exhaustion of neurocytes, toxicity of excitatory neurotransmitter glutamate, calcium overload, delayed cell death, free radical damage, release of different cytokines, depolarization of ischemic penumbra and inflammatory reaction. All those complicated pathological changes lead to the activation of CaMKs, ERK, p38 and JNK (the MAPKs signal transduction pathway consists of the latter three).
Epidemiological studies show that the prevalence of dementia in ischemic stroke patients is remarkably higher than in control subjects. Many of these dementias develop progressively, and cerebral damage is not the direct cause of the subsequent dementia in over half of these cases. Alzheimer's Disease (AD) is a degenerative change and the most common cause of senile dementia, which is mainly characterized by the progressive memory loss and cognitive handicap of the patients. neurofilament tangles(NFTs) formation, loss of cortical neurons and sinile plaques are the major pathological features of AD.So far AD remains to be idiopathic. Multiple gene locus abnormalities were found in familial AD cases, whereas the mechanism of sporadic cases may be associated with cerebral I/R injury. Cerebral ischemia, hypoxia and free radical damage may be the main causes of AD[7].
Vascular risk factors of stroke can also increase the risk of AD, and adequate perfusion of brain can relieve the symptoms of AD remarkably. Moreover, AD and cerebral vascular diseases (CVD) are found to share similar neuropathological features such as aberrant hyperphosphorylation of tau protein and neuron necrosis. However, it is not yet clear whether the neuropathological changes of AD take place after cerebral ischemia occurs, so it has special importance to clarify whether AD-like pathological changes can be induced by cerebral ischemia/reperfusion.
Tau protein is an microtubule-associated protein widely expressed in nervous system, which plays an important role in stabling microtubules, promoting microtubule assembly,maintaining neuronal morphology and advancing the axonal transportation. The modification of tau protein may be the essential link in neuronal dysfunction and death, for the balance between phosphorylation and dephosphorylation of which is the critical factor to maintain the stability of microtubule. The hyperphosphorylation of tau protein is the characteristic patholobical change in certain nervous system degenerative diseases such as AD、Pick disease. Exceptionally in AD, paired helical filaments (PHFs) are found to contain a significant amount of tau antibodies specific for a phosphorylated form, and then aggregate into NFTs(neurofilament tangles), the hallmark of the disease. It is learned that there are more than 21 phosphorylation sites in tau protein, however,the majority are Thr231, Ser396, Ser404, Ser199, Ser202, Thr205, Ser262 and so on. The hyperphosphorylation of these sites are mainly regulated by protein kinase GSK-3β, cdk5 and MAPK.
JNK is one kind of stressor-activated Serine/threonine protein kinases which can phosphorylate the amino activation area of nuclear transcription factor c-Jun. JNK/ SAPK is one of the important signal transduction pathways of MAPKs, which plays an important role in the pathogenesis of AD.It is now found that the pathway can phosphorylate the sites of tau protein mainly through Thr205, Ser396, Ser422, Ser202、Ser404、Ser199、Thr212、Thr231. The hyperphosphorylation of tau protein is considered the early event of AD, which is the key to the formation of NFTs, and is concerned with the neuron loss of the disease. The JNK/SAPK signal transduction pathway is actived during after cerebral ischemia-reperfusion injury. However, it is still unclear what is the function of JNK in tau protein abnormal hyperphosphorylation after focal cerebral ischemia.
When cerebral Infarcted,the regional center of cerebral blood vessels dominant will form the core area and the surrounding ischemic penumbra, neuronal necrosisis are mainly in the former, while the latter is composed of neuronal apoptosis and is the key point to protect. The expression of apoptosis related genes, bcl-2 and bax, is correlated with hyperphosphorylated tau protein positive cells. bcl-2 and bax expression changes after cerebral ischemia. JNK is the critical regulator of neuronal apoptosis after cerebral ischemia-reperfusion injury. bax is the main pro-apoptotic genes which JNK regulats to induce apoptosis of neural cells during cerebral ischemia-reperfusion injury. Cerebral ischemia induces the aberrant hyperphosphorylation of tau protein as well. So we presume that the post-ischemic neurocyte apoptosis may have correlation with the aberrant hyperphosphorylation of tau protein, and they may share the same process with AD by regulating the apoptosis related genes bcl-2 and bax. JNK may induce AD's progression through hyperphosphorylation of tau protein and neurocyte apoptosis after cerebral ischemia.
This study we established the model of middle cerebral artery occlusion of rats and examined specific phosphorylation sites of tau protein and the degree of phosphorylation, the solubility of phosphorylated tau protein, all of which was to discuss the relationship between brain stroke and AD. Furthermore, we studied the function of JNK in hyperphosphorylation of tau protein and expression of bcl-2, bax after cerebral ischemia, and the relationship between tau phosphorylation and post-ischemic neuronal apoptosis. In the last, we observed the effects of JNK in the infraction volume after cerebral ischemia-reperfusion by blocking the activity of JNK, The aims were to clarify the function of JNK in the phosphorylation of tau protein and neuronal apoptosis after brain ischemia.
Objective:To establish rodent models of local cerebral ischemia/reperfusion through the modified thread occlusion method of MCAO and to evaluate the validity and stability of this model for the following research. Methods:A 3-0 monofilament nylon suture was introduced into the internal carotid artery (ICA) lumen through a puncture at the common carotid artery (CCA). With a depth of (20±3)mm, the suture could reach the initiation part of the anterior cerebral artery (ACA) and embolize this vessel, leading to local cerebral ischemia. The validity and stability of this model were evaluated though TTC staining and neurological grading scale. Results:The general conditions of successful models were bad. The infarction focus was obvious under TTC staining. Results were stable and little variation was observed. Excluding the minority of failed models, all rodents were scored 1-3 according to neurological grading scale. Conclusion:Modified MCAO method has relatively mild damage, more stable results and a higher repeatability, which provides a reliable guarantee for the following research.
Objective:To explore the changes of tau protein phosphorylation in rat parietal cortex neurons after focal cerebral ischemia-reperfusion (I/R) and to clarify the relationship between cerebral infarction and Alzheimer's disease. Methods:The rat focal cerebral ischemia-reperfusion model was induced by occlusion of the right middle cerebral artery using the intraluminal suture method. The level of tau hyperphosphorylation at Ser199/202, Ser396, Ser404 and Thr231 sites and total tau in rat parietal cortex during focal cerebral ischemia/reperfusion were detected by and Western blot. Results:The levels of tau hyperphosphorylation at Ser199/202, Ser396, Ser404 and Thr 231 sites were significantly higher in I/R. group than those in the sham group, but the total tau did not increase. Conclusion:The cerebral infarction may contribute to Alzheimer's disease occurrence and development.
Objective:To investigate the function of JNK in hyperphosphorylation of tau protein and expression of bcl-2, bax after cerebral ischemia, and the relationship between tau phosphorylation and post-ischemic neuronal apoptosis. In the last, we observed the effects of JNK in the infraction volume after cerebral ischemia-reperfusion by blocking the activity of JNK, and to clarify the function of JNK in the phosphorylation of tau protein and neuronal apoptosis after brain ischemia. Methods:The rat focal cerebral ischemia-reperfusion model was induced by occlusion of the right middle cerebral artery using the intraluminal suture method. The level of JNK activity, tau hyperphosphorylation at Ser396 and Thr231、Serl 99/202、Ser404 sites and the expressions of bcl-2, bax during focal cerebral ischemia/reperfusion were detected by Western blot. The relationship between the phosphorylated tau protein and the exression of bax were checked out by immunofluorescence method. The effect of JNK activity on infarction volume was tested by TTC method. Results:The activity of JNK were significantly higher in I/R groups than that in the control groups after ischemia-reperfusion.When the activity of JNK was inhibited by SP600125,the level of tau hyperphosphorylation at Ser396 and Thr231、Ser199/202、Ser404 sites,the expression of bax and the infarct volume notably reduced after ischemia-reperfusion. bax expression and the tau protein hyperphosphorylation were co-localized. Conclusion:JNK plays an important role in Alzheimer's like disease pathology change after cerebral ischemia and reperfusion. It can be used as as a therapeutic target of dementia after cerebral ischemia.
随着社会发展和人类饮食结构的改变,脑血管病的发病率呈明显上升趋势,世界范围内脑卒中的发病率为150-200／10万人,其中缺血性脑卒中高达85%。在我国每年新发脑卒中约200万例,每年死于脑血管病约150万例。在神经外科也广泛存在脑缺血性损伤如：脑外伤后并发的缺血性脑损伤,颅内动脉瘤夹闭术中误夹载瘤动脉或术后血管痉挛造成的缺血性损伤以及术中控制性降压不当导致的脑缺血损伤等。缺血性脑卒中的血管阻塞导致的急性脑缺血需要迅速的血管再通,而脑血流的再灌注会导致脑组织缺血再灌注损伤。脑缺血再灌注损伤主要涉及神经细胞能量耗竭、兴奋性谷氨酸神经递质毒性、钙离子超载、迟发性细胞死亡、自由基损伤、各种细胞因子的释放、半暗带区的去极化以及炎症反应等。这些复杂的病理变化导致钙调节蛋白依赖性激酶(CaMKs)和有丝分裂原激活蛋白(MAPKs)信号转导通路：细胞外信号调节激酶(ERK),p38和c-Jun氨基末端激酶(JNK)的激活。
流行病学调查发现脑卒中明显增加了痴呆的发病率,这些痴呆患者的病情多呈进行性发展,而且一半以上患者发生的继发性痴呆不是脑卒中脑损害直接导致的。阿尔茨海默病(Alzheimer's Disease, AD)是一种退行性病变,它是引起老年痴呆的最常见病因,临床症状主要是进行性记忆力丧失和认知功能障碍,病理学上主要表现为神经纤维缠结形成以及皮质神经元的丢失和老年斑的生成。AD的病因至今不明,发现家族性AD存在多个基因位点的异常,而散发性AD的发病机制比较复杂可能与脑缺血再灌注损伤有关,脑缺血、缺氧和自由基损伤可能是AD发生的重要病因。脑卒中的血管危险因素可使AD的患病风险增高,增加脑供血改善脑灌注不足可以明显改善AD的临床症状,并且脑血管疾病和AD之间存在相似的神经病理学特征如：脑缺血和AD中都存在tau蛋白的高度异常磷酸化和神经元的凋亡。但脑缺血后是否发生了和AD一样神经病理学特征目前还不清楚。因此进一步证实脑缺血再灌注损伤后是否发生AD样病理变化对阐明脑缺血和AD之间的关系是很有意义的。
tau蛋白是一种在神经系统广泛表达的微管相关蛋白,具有稳定微管,促进微管装配、维持神经元的形态和促进轴突运输的重要作用。tau蛋白功能异常改变可能是神经元功能障碍和死亡的必要环节。tau蛋白的磷酸化和去磷酸化间平衡是维持微管稳定性的关键调控因素,tau蛋白的高度异常磷酸化是神经系统退行性病变如：AD、皮克病(Pick's disease)等的特征性病理变化。在AD中tau蛋白的过度异常磷酸化导致tau蛋白自身聚集成双螺旋纤维细丝(paired helical filament, PHF),进而产生具有阿尔茨海默病特征性病理改变-神经纤维缠结(neurofilament tangles, NFTs)。目前发现tau蛋白的磷酸化位点多达21个,主要的磷酸化位点是Thr231、Ser396、Ser404、Ser199、Ser202、Thr205、Ser262等。这些位点的过度磷酸化主要有蛋白激酶GSK-3β、cdk5和MAPK来调节的。
JNK/SAPK是MAPKs的一条重要信号转导通路之一,JNK是上世纪90年代早期发现的能被许多应激因子激活,且能使核转录因子c-Jun的氨基活化区磷酸化的丝氨酸／苏氨酸蛋白激酶。它在AD的发病机制中具有重要作用,目前发现其能磷酸化tau蛋白的位点主要有Thr205、Ser396、Ser422、Ser202、Ser404、Ser199、Thr212、Thr231。tau蛋白的异常磷酸化是AD病的早期事件,它被认为是NFTs形成的关键,并且其与AD中神经元的丢失有关。JNK信号转导通路在局灶性脑缺血再灌注损伤后被激活,但JNK在局灶性脑缺血后tau蛋白异常过度磷酸化中的作用目前还不清楚。
脑梗塞时血管支配的区域中心就会形成缺血核心区和周边的半影区,核心区以神经元坏死为主,半影区则以神经元凋亡为主。而缺血的半影区是神经元保护的关键点。在AD中凋亡相关基因bcl-2、bax的表达和高度磷酸化的tau蛋白阳性细胞存在相关关系,同样bcl-2、bax在脑缺血后的表达也发生变化。JNK是脑缺血再灌注损伤后神经细胞凋亡的主要调节因子,bax是JNK在脑缺血再灌注损伤后调节神经细胞凋亡的主要促凋亡基因,而脑缺血再灌注后又诱导了tau蛋白的异常高度磷酸化。因此我们推测脑缺血后神经细胞的凋亡可能与高度异常磷酸化的tau蛋白相关,它们可能与AD一样是通过调节相同的凋亡相关基因bcl-2、bax来实现的,脑缺血后JNK有可能导致tau蛋白的高度异常磷酸化引发细胞凋亡进而发生AD样病变值得探讨。
故本研究利用大鼠大脑中动脉栓塞模型研究脑缺血后在AD患者脑中具有特征性的tau蛋白异常过度磷酸化位点的磷酸化变化,磷酸化tau蛋白的溶解性以进一步阐明脑缺血和阿尔茨海默病的关系。并且研究JNK在脑缺血再灌注损伤后tau蛋白异常过度磷酸化和凋亡相关基因bcl-2、bax的表达之间的联系,以及脑缺血再灌注损伤后异常过度磷酸化的tau蛋白和bax的表达空间关系并检测阻断JNK的活性后对脑缺血再灌注后梗塞灶体积的影响,进一步阐明JNK在脑缺血损伤后tau蛋白磷酸化和神经细胞凋亡中的作用。
目的：应用改良的MCAO线栓法制作大鼠局灶性脑缺血再灌注模型,并评价该模型的效果、稳定性为后继实验奠定基础。方法：将3-0尼龙线插入CCA内,并不断调整栓塞线进入的角度使其顺利进入ICA,前端到达大脑前动脉的起始部,通过阻断大脑中动脉的血供而造成大脑中动脉供血区脑缺血,栓塞线进入深度约(20±3)mm。并应用TTC染色及神经功能学评分评估大鼠局灶性脑缺血再灌注模型的效果及稳定性。结果：造模成功者一般状况较差,TTC染色发现梗塞灶明显、稳定性好,变异较小。除少数动物造模死亡外,其余神经功能学评分都在1-3分之间。结论：改良的MCAO线栓模型创伤小；实验结果稳定、可重复性强,为脑缺血再灌注实验提供有力保障。
目的：探讨局灶性脑缺血再灌注后大鼠皮质神经元tau蛋白磷酸化的变化,以阐明脑梗死和阿尔茨海默病间的关系。方法：制作局灶性脑缺血再灌注模型,应用免疫印迹法检测局灶性脑缺血再灌注后大鼠顶叶皮质tau蛋白在Ser199/202、Ser396、Ser404和Thr231位点磷酸化和非溶性磷酸化tau蛋白的变化。结果：脑缺血再灌注6h后皮质tau蛋白在Serl99/202、Ser396、Ser404和Thr231位点发生异常高度磷酸化,非溶性磷酸化tau蛋白显著增加。结论：脑缺血再灌注后发生阿尔茨海默病样病理变化,脑梗死可能促进阿尔茨海默病的发生、发展。
目的：探讨JNK在局灶性脑缺血再灌注后大鼠皮质神经元的tau蛋白过度磷酸化和bcl-2、bax的表达中的作用,以及脑缺血再灌注损伤后异常过度磷酸化的tau蛋白和bax的空间关系并检测阻断JNK的活性后对脑缺血再灌注后梗塞灶体积的影响,进一步阐明JNK在脑缺血损伤后tau蛋白磷酸化和神经细胞凋亡中的作用。方法：制作局灶性脑缺血再灌注模型,应用免疫印迹检测JNK的活性变化以及应用其特异性阻断剂SP600125阻断JNK的活性后大鼠顶叶皮质tau蛋白在Ser396和Thr231、Ser199/202、Ser404位点磷酸化的变化；免疫荧光双标法分别检测脑缺血再灌注后bax的表达和磷酸化tau蛋白的关系,应用TTC法检测SP600125对梗塞灶体积的影响。结果：脑缺血再灌注损伤后JNK的活性增加,应用SP600125阻断JNK的活性后显著抑制脑缺血再灌注后tau蛋白在Ser396和Thr231、Serl99/202、Ser404位点的磷酸化和促凋亡蛋白bax的表达,并且明显减小梗塞灶的体积。脑缺血再灌注后bax的表达与tau蛋白高度磷酸化存在显著相关性。结论：JNK在脑缺血再灌注后阿尔茨海默病样病理变化中起了重要作用,其可作为脑缺血再灌注后痴呆的一个治疗靶点。
Research Background
Along with the social development and the changing of human dietary structure, the prevalence of cerebral vascular disease has increased gradually. The worldwide incidence of stroke is 150-200/100,000, up to 85% of which is ischemic. There are about 2 million cases of new-onset stroke in our country annually, and 1.5 million domestic patients die of CVD every year. Cerebral ischemic injury are also found extensively in the neurosurgical practice, such as brain trauma complicated with cerebral ischemia, vasospasm after the aneurysm incarcerated operation and wrongly clipping of the parent artery or inappropriate controlled hypotension during the operation. The acute ischemia usually suggests a timely repatency, which can aggravate the ischemia in return.
The mechanism of cerebral ischemic/reperfusive injury is mainly associated with the energy exhaustion of neurocytes, toxicity of excitatory neurotransmitter glutamate, calcium overload, delayed cell death, free radical damage, release of different cytokines, depolarization of ischemic penumbra and inflammatory reaction. All those complicated pathological changes lead to the activation of CaMKs, ERK, p38 and JNK (the MAPKs signal transduction pathway consists of the latter three).
Epidemiological studies show that the prevalence of dementia in ischemic stroke patients is remarkably higher than in control subjects. Many of these dementias develop progressively, and cerebral damage is not the direct cause of the subsequent dementia in over half of these cases. Alzheimer's Disease (AD) is a degenerative change and the most common cause of senile dementia, which is mainly characterized by the progressive memory loss and cognitive handicap of the patients. neurofilament tangles(NFTs) formation, loss of cortical neurons and sinile plaques are the major pathological features of AD.So far AD remains to be idiopathic. Multiple gene locus abnormalities were found in familial AD cases, whereas the mechanism of sporadic cases may be associated with cerebral I/R injury. Cerebral ischemia, hypoxia and free radical damage may be the main causes of AD[7].
Vascular risk factors of stroke can also increase the risk of AD, and adequate perfusion of brain can relieve the symptoms of AD remarkably. Moreover, AD and cerebral vascular diseases (CVD) are found to share similar neuropathological features such as aberrant hyperphosphorylation of tau protein and neuron necrosis. However, it is not yet clear whether the neuropathological changes of AD take place after cerebral ischemia occurs, so it has special importance to clarify whether AD-like pathological changes can be induced by cerebral ischemia/reperfusion.
Tau protein is an microtubule-associated protein widely expressed in nervous system, which plays an important role in stabling microtubules, promoting microtubule assembly,maintaining neuronal morphology and advancing the axonal transportation. The modification of tau protein may be the essential link in neuronal dysfunction and death, for the balance between phosphorylation and dephosphorylation of which is the critical factor to maintain the stability of microtubule. The hyperphosphorylation of tau protein is the characteristic patholobical change in certain nervous system degenerative diseases such as AD、Pick disease. Exceptionally in AD, paired helical filaments (PHFs) are found to contain a significant amount of tau antibodies specific for a phosphorylated form, and then aggregate into NFTs(neurofilament tangles), the hallmark of the disease. It is learned that there are more than 21 phosphorylation sites in tau protein, however,the majority are Thr231, Ser396, Ser404, Ser199, Ser202, Thr205, Ser262 and so on. The hyperphosphorylation of these sites are mainly regulated by protein kinase GSK-3β, cdk5 and MAPK.
JNK is one kind of stressor-activated Serine/threonine protein kinases which can phosphorylate the amino activation area of nuclear transcription factor c-Jun. JNK/ SAPK is one of the important signal transduction pathways of MAPKs, which plays an important role in the pathogenesis of AD.It is now found that the pathway can phosphorylate the sites of tau protein mainly through Thr205, Ser396, Ser422, Ser202、Ser404、Ser199、Thr212、Thr231. The hyperphosphorylation of tau protein is considered the early event of AD, which is the key to the formation of NFTs, and is concerned with the neuron loss of the disease. The JNK/SAPK signal transduction pathway is actived during after cerebral ischemia-reperfusion injury. However, it is still unclear what is the function of JNK in tau protein abnormal hyperphosphorylation after focal cerebral ischemia.
When cerebral Infarcted,the regional center of cerebral blood vessels dominant will form the core area and the surrounding ischemic penumbra, neuronal necrosisis are mainly in the former, while the latter is composed of neuronal apoptosis and is the key point to protect. The expression of apoptosis related genes, bcl-2 and bax, is correlated with hyperphosphorylated tau protein positive cells. bcl-2 and bax expression changes after cerebral ischemia. JNK is the critical regulator of neuronal apoptosis after cerebral ischemia-reperfusion injury. bax is the main pro-apoptotic genes which JNK regulats to induce apoptosis of neural cells during cerebral ischemia-reperfusion injury. Cerebral ischemia induces the aberrant hyperphosphorylation of tau protein as well. So we presume that the post-ischemic neurocyte apoptosis may have correlation with the aberrant hyperphosphorylation of tau protein, and they may share the same process with AD by regulating the apoptosis related genes bcl-2 and bax. JNK may induce AD's progression through hyperphosphorylation of tau protein and neurocyte apoptosis after cerebral ischemia.
This study we established the model of middle cerebral artery occlusion of rats and examined specific phosphorylation sites of tau protein and the degree of phosphorylation, the solubility of phosphorylated tau protein, all of which was to discuss the relationship between brain stroke and AD. Furthermore, we studied the function of JNK in hyperphosphorylation of tau protein and expression of bcl-2, bax after cerebral ischemia, and the relationship between tau phosphorylation and post-ischemic neuronal apoptosis. In the last, we observed the effects of JNK in the infraction volume after cerebral ischemia-reperfusion by blocking the activity of JNK, The aims were to clarify the function of JNK in the phosphorylation of tau protein and neuronal apoptosis after brain ischemia.
Objective:To establish rodent models of local cerebral ischemia/reperfusion through the modified thread occlusion method of MCAO and to evaluate the validity and stability of this model for the following research. Methods:A 3-0 monofilament nylon suture was introduced into the internal carotid artery (ICA) lumen through a puncture at the common carotid artery (CCA). With a depth of (20±3)mm, the suture could reach the initiation part of the anterior cerebral artery (ACA) and embolize this vessel, leading to local cerebral ischemia. The validity and stability of this model were evaluated though TTC staining and neurological grading scale. Results:The general conditions of successful models were bad. The infarction focus was obvious under TTC staining. Results were stable and little variation was observed. Excluding the minority of failed models, all rodents were scored 1-3 according to neurological grading scale. Conclusion:Modified MCAO method has relatively mild damage, more stable results and a higher repeatability, which provides a reliable guarantee for the following research.
Objective:To explore the changes of tau protein phosphorylation in rat parietal cortex neurons after focal cerebral ischemia-reperfusion (I/R) and to clarify the relationship between cerebral infarction and Alzheimer's disease. Methods:The rat focal cerebral ischemia-reperfusion model was induced by occlusion of the right middle cerebral artery using the intraluminal suture method. The level of tau hyperphosphorylation at Ser199/202, Ser396, Ser404 and Thr231 sites and total tau in rat parietal cortex during focal cerebral ischemia/reperfusion were detected by and Western blot. Results:The levels of tau hyperphosphorylation at Ser199/202, Ser396, Ser404 and Thr 231 sites were significantly higher in I/R. group than those in the sham group, but the total tau did not increase. Conclusion:The cerebral infarction may contribute to Alzheimer's disease occurrence and development.
Objective:To investigate the function of JNK in hyperphosphorylation of tau protein and expression of bcl-2, bax after cerebral ischemia, and the relationship between tau phosphorylation and post-ischemic neuronal apoptosis. In the last, we observed the effects of JNK in the infraction volume after cerebral ischemia-reperfusion by blocking the activity of JNK, and to clarify the function of JNK in the phosphorylation of tau protein and neuronal apoptosis after brain ischemia. Methods:The rat focal cerebral ischemia-reperfusion model was induced by occlusion of the right middle cerebral artery using the intraluminal suture method. The level of JNK activity, tau hyperphosphorylation at Ser396 and Thr231、Serl 99/202、Ser404 sites and the expressions of bcl-2, bax during focal cerebral ischemia/reperfusion were detected by Western blot. The relationship between the phosphorylated tau protein and the exression of bax were checked out by immunofluorescence method. The effect of JNK activity on infarction volume was tested by TTC method. Results:The activity of JNK were significantly higher in I/R groups than that in the control groups after ischemia-reperfusion.When the activity of JNK was inhibited by SP600125,the level of tau hyperphosphorylation at Ser396 and Thr231、Ser199/202、Ser404 sites,the expression of bax and the infarct volume notably reduced after ischemia-reperfusion. bax expression and the tau protein hyperphosphorylation were co-localized. Conclusion:JNK plays an important role in Alzheimer's like disease pathology change after cerebral ischemia and reperfusion. It can be used as as a therapeutic target of dementia after cerebral ischemia.
引文
[1]饶明俐,中国脑血管病防治指南(J Apoplexy and Nervous Disease October) 2005,122:5.
[2]Mayer TE, Hamann GF, Baranczyk J, et al. Dynamic CT perfusion imaging of acute stroke. AJNR Am J Neuroradiol [J].2000,21 (8):144-9.
[3]Kalaria R. Similarities between Alzheimer's disease and vascular dementia [J]. J Neurol Sci,2002,203/204:29-34.
[4]Tatemichi T K, Desmond D W, Mayeux R, et al. Dementia after stroke:baseline frequency, risks, and clinical features in a hospitalized cohort[J]. Neurology,1992, 42 (6):1185-1193.
[5]Tatemichi T K, Paik M, Bagiella E, et al. Risk of dementia after stroke in a hospitalized cohort:results of a longitudinal study [J]. Neurology,1994,44 (10): 1885-1891.
[6]Ariga T, McDonald MP, Yu RK, et al. Role of ganglioside metabolism in the pathogenesis of Alzheimer's disease-a review [J]. J Lipid Res,2008,49 (6):1157-1175.
[7]Bennett SA, Pappas BA, Stevens WD, et al. Cleavage of amyloid precursor protein elicited by chronic cerebral hypoperfusion [J]. Neurobiol Aging,2000,21 (2):207-214.
[8]De la Torre J C. Is Alzheimer's disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics [J]. Lancet Neurol,2004,3 (3):184-190.
[9]Pluta R. From brain ischemia-reperfusion injury to possible sporadic Alzheimer's disease [J]. Curr Neurovasc Res,2004,1 (5):441-453.
[10]Gotz J, Chen F, van Dorpe J, et al. Formation of neurofibrillary tangles in P3011 tau transgenic mice induced by Abeta 42 fibrils [J]. Science,2001,293 (5534): 1446-1447.
[11]Pulverer BJ, Kyriakis JM, Avruch J, et al. Phosphorylation of c-jun mediated by MAP kinases [J]. Nature,1991,353 (6345):670-673.
[12]Fujimura M, Usuki F, Sawada M, et al. Methylmercury induces neuropathological changes with tau hyperphosphorylation mainly through the activation of the c-jun-N-terminal kinase pathway in the cerebral cortex, but not in the hippocampus of the mouse brain [J]. NeuroToxicology,2009,30 (6):1000-1007.
[13]Yoshida H, Hastie CJ, McLauchlan H, et al. Phosphorylation of microtubule-associated protein tau by isoforms of c-Jun N-terminal kinase (JNK) [J]. Journal of Neurochemistry,2004,90 (2):352-358.
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[16]Gao Y, Signore AP, Yin W, et al. Neuroprotection against focal ischemic brain injury by inhibition of c-Jun N-terminal kinase and attenuation of the mitochondrial apoptosis-signaling pathway [J]. Journal of Cerebral Blood Flow & Metabolism, 2005,25 (6):694-712.
[17]Lei K, Nimnual A, Zong WX, et al. The Bax subfamily of Bcl2-related proteins is essential for apoptotic signal transduction by c-Jun NH (2)-terminal kinase [J]. Molecular and Cellular Biology,2002,22 (13):4929-4942.
[18]Smith WS. Pathophysiology of focal cerebral ischemia:a therapeutic perspective [J]. Journal of Vascular and Interventional Radiology,2004,15 (1 Pt 2):S3-S12.
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[20]MacGibbon GA, Lawlor PA, Sirimanne ES, et al. Bax expression in mammalian neurons undergoing apoptosis, and in Alzheimer's disease hippocampus [J]. Brain Res,1997,750 (1-2):223-234.
[21]Tortosa A, Lopea E, Ferrer I. Bcl-2 and Bax protein expression in Alzheimer's disease [J]. Acta Neuropathol,1998,95:407-412.
[22]Zhao H,Yenari MA,Cheng D, et al. Bcl-2 overexpression protects against neuron loss within the ischemic margin following experimental stroke and inhibits cytochrome c translocation and caspase-3 activity [J]. J Neurochem,2003,85(4): 1026-1036.
[23]Zhu Y, Prehn J, Clumsee C, et al. The beta-2-adrnoceptor agonist clenbuterol modulates Bcl-2, Bcl-xl and Bax protein expression following transient forebrain ischemia [J]. Neuroscience 1999,90(4):1255-63.
[1]Rao ML, et al. Chinese Cerebrovascular Disease Contro Guide (J Apoplexy and Nervous Disease October),2005,122:5. (Chinese)
[2]Mayer TE, Hamann GF, Baranczyk J, et al. Dynamic CT perfusion imaging of acute stroke. AJNR Am J Neuroradiol [J].2000,21 (8):1441-9.
[3]Kalaria R. Similarities between Alzheimer's disease and vascular dementia [J]. J Neurol Sci,2002,203/204:29-34.
[4]Tatemichi T K, Desmond D W, Mayeux R, et al. Dementia after stroke:baseline frequency, risks, and clinical features in a hospitalized cohort[J]. Neurology,1992, 42(6):1185-1193.
[5]Tatemichi T K, Paik M, Bagiella E, et al. Risk of dementia after stroke in a hospitalized cohort:results of a longitudinal study [J]. Neurology,1994,44 (10): 1885-1891.
[6]Ariga T, McDonald MP, Yu RK, et al. Role of ganglioside metabolism in the pathogenesis of Alzheimer's disease-a review [J]. J Lipid Res,2008,49 (6): 1157-1175.
[7]Bennett SA, Pappas BA, Stevens WD, et al. Cleavage of amyloid precursor protein elicited by chronic cerebral hypoperfusion [J]. Neurobiol Aging,2000,21 (2):207-214.
[8]De la Torre J C. Is Alzheimer's disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics [J]. Lancet Neurol,2004,3 (3):184-190.
[9]Pluta R. From brain ischemia-reperfusion injury to possible sporadic Alzheimer's disease [J]. Curr Neurovasc Res,2004,1 (5):441-453.
[10]Gotz J, Chen F, van Dorpe J, et al. Formation of neurofibrillary tangles in P3011 tau transgenic mice induced by Abeta 42 fibrils [J]. Science,2001,293 (5534): 1446-1447.
[11]Pulverer BJ, Kyriakis JM, Avruch J, et al. Phosphorylation of c-jun mediated by MAP kinases [J]. Nature,1991,353 (6345):670-673.
[12]Fujimura M, Usuki F, Sawada M, et al. Methylmercury induces neuropathological changes with tau hyperphosphorylation mainly through the activation of the c-jun-N-terminal kinase pathway in the cerebral cortex, but not in the hippocampus of the mouse brain [J]. NeuroToxicology,2009,30 (6):1000-1007.
[13]Yoshida H, Hastie CJ, McLauchlan H, et al. Phosphorylation of microtubule associated protein tau by isoforms of c-Jun N-terminal kinase (JNK) [J]. Journal of Neurochemistry,2004,90 (2):352-358.
[14]Wu Q, qian CY. The research of Alzheimer disease neurofibrillary tangles and tau proteins [J]. Chinese Journal of Nervous and Mental.2000,26 (1):63-64. (Chinese)
[15]Okuno S, Saito A, Hayashi T, et al. The c-Jun N-terminal protein kinase signaling pathway mediates Bax activation and subsequent neuronal apoptosis through interaction with Bim after transient focal cerebral ischemia [J]. J Neurosci 2004,24 (36):7879-7887.
[16]Gao Y, Signore AP, Yin W, et al. Neuroprotection against focal ischemic brain injury by inhibition of c-Jun N-terminal kinase and attenuation of the mitochondrial apoptosis-signaling pathway [J]. Journal of Cerebral Blood Flow & Metabolism,2005, 25 (6):694-712.
[17]Lei K, Nimnual A, Zong WX, et al. The bax subfamily of Bcl2-related proteins is essential for apoptotic signal transduction by c-Jun NH(2)-terminal kinase [J]. Molecular and Cellular Biology,2002,22 (13):4929-4942.
[18]Smith WS. Pathophysiology of focal cerebral ischemia:a therapeutic perspective [J]. Journal of Vascular and Interventional Radiology,2004,15 (1 Pt 2):S3-S12.
[19]Zhang M, et al. Apoptosis and apoptosis-related genes after cerebral ischemia [J]. Chinese Journal of Clinical Rehabilitation.2004,8 (25):5334-5335. (Chinese)
[20]MacGibbon GA, Lawlor PA, Sirimanne ES, et al. Bax expression in mammalian neurons undergoing apoptosis, and in Alzheimer's disease hippocampus [J]. Brain Res,1997,750(1-2):223-234.
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