阿尔茨海默症小鼠对脑缺血损伤易感性的研究

发布时间：2018-04-06 00:23

本文选题：脑缺血　切入点：阿尔茨海默症　出处：《兰州大学》2014年硕士论文

【摘要】：阿尔茨海默症(AD)和脑缺血是世界范围内引发死亡的两大主要原因,两者之间有着诸多关联,AD可导致脑中风的易感性就是其中之一。这种易感性不仅体现在AD患者得中风的风险更高,更体现在患AD后再中风会引发更严重的损伤。目前分别对于AD和脑缺血的研究有很多,但是AD对脑缺血损伤易感性的机理尚不清楚。随着我国人均寿命的增长和老龄化社会的到来,了解这一机制就显得尤为重要。本实验利用早老型的APP/PS1转基因小鼠分别与荧光标记神经元或小胶质细胞的小鼠杂交,培育出神经元或小胶质细胞带有荧光标记的AD小鼠。通过构建急性脑缺血模型,运用行为学方法和组织学手段,研究了阿尔茨海默症小鼠在脑缺血损伤后的病理变化以及易感机理。研究结果表明相比于野生型(WT)小鼠,AD小鼠的大脑本身就有诸多不同之处：大脑皮层和海马区分布着p淀粉样聚集而成的老年斑,老年斑周围的小胶质细胞和星形胶质细胞呈活化状态,神经元树突末端肿大。在脑缺血后第3天,8月龄以上AD小鼠的转棒坚持时间和前肢抓力的降幅更大；AD小鼠比同月龄的WT小鼠具有更大的梗死体积百分比；免疫组化染色观察到AD大脑中星形胶质细胞在脑缺血的病理进程中活化异常；通过双光子活体观测手段和伊文思蓝渗漏量的检测方法发现AD小鼠脑缺血后血脑屏障渗漏剧烈；同时运用蛋白质印迹法检测出AD脑缺血半脑皮层的紧密连接蛋白claudin-5的含量显著降低,进一步证明了AD小鼠脑缺血后血脑屏障溃解严重。本文的研究结果揭示了阿尔茨海默症小鼠的血脑屏障在受到缺血性脑中风冲击后更易受损,可能与AD对脑缺血损伤的易感性有关。这些发现不仅有助于深入了解AD和脑缺血的病理进程,揭示AD的脑缺血易感性的机理,而且可以为AD和脑缺血的治疗提供新的思路和理论依据。
[Abstract]:Alzheimer's disease (AD) and cerebral ischemia are two major causes of death worldwide.This susceptibility is reflected not only in AD patients' higher risk of stroke, but also in the risk of more severe damage caused by stroke after AD.At present, there are many researches on AD and cerebral ischemia, but the mechanism of AD susceptibility to cerebral ischemia injury is not clear.With the increase of life expectancy and the arrival of aging society, it is very important to understand this mechanism.In this experiment, APP/PS1 transgenic mice of early age were hybridized with fluorescent labeled neurons or microglial cells respectively, and AD mice with fluorescent labeled neurons or microglia were bred.The acute cerebral ischemia model was established and the pathological changes and susceptibility mechanism of Alzheimer's disease mice after cerebral ischemia were studied by means of behavioral and histological methods.The results showed that the brains of AD mice were different from those of wild-type WT-mice: amyloid amyloid plaques were distributed in the cortex and hippocampus.The microglia and astrocytes around the senile plaque were activated and the terminal dendrites of neurons were enlarged.On the 3rd day after cerebral ischemia, AD mice over 8 months of age had a larger percentage of infarct volume than WT mice of the same age.The activation of astrocytes in the brain of AD was abnormal in the pathological process of cerebral ischemia by immunohistochemical staining, and the blood brain barrier leakage was found to be severe in AD mice after cerebral ischemia by two photon in vivo observation and the detection of Evans blue leakage.At the same time, the content of tight junction protein (claudin-5) in cerebral ischemic cerebral cortex of AD mice was significantly decreased by Western blotting, which further proved that the breakdown of blood-brain barrier was serious in AD mice after cerebral ischemia.The results of this study suggest that the blood-brain barrier in Alzheimer's mice is more vulnerable to ischemic stroke, which may be related to the susceptibility of AD to cerebral ischemic injury.These findings not only help to understand the pathological process of AD and cerebral ischemia, but also provide new ideas and theoretical basis for the treatment of AD and cerebral ischemia.
【学位授予单位】：兰州大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R749.16;R743

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