慢性脑缺血对APP/PS1双转基因小鼠行为学及脑组织形态学的影响

Effect of chronic cerebral ischemia on the behavior and brain morphology of APP/PS1 double transgenic mice

摘要:

目的：探讨慢性脑缺血对APP/PS1双转基因阿尔茨海默病（Alzheimer’s disease，AD）模型小鼠的行为学以及脑组织形态学的影响。方法：将20只3月龄APP/PS1 AD模型小鼠随机分成２组，每组10只，对其中一组采用改良的双侧颈总动脉狭窄术，另一组双侧颈总动脉未结扎小鼠为假手术对照组。术后1个月分别采用Morris水迷宫、组织学和免疫组化染色，检测模型组和假手术组小鼠行为学的改变、海马区神经细胞形态学的改变、海马区神经细胞内NeuN和APP及Aβ的表达变化。结果：行为学实验结果：（1）可视平台下，２组小鼠找到平台的时间（t=1.31，P=0.19）及搜索的平均路程（t=0.04，P=0.97）无显著差异；（2）隐蔽平台下，脑缺血模型组小鼠（26.39±1.37）找到平台的时间较假手术对照组（20.19±1.19）明显延长（t=3.44，P=0.00）；（3）空间探索实验中，经过平台的次数，脑缺血模型组小鼠（3.11±0.37）较对照组（4.25±0.34）明显减少（t=2.24，P=0.03）。HE染色：脑缺血模型组小鼠海马内神经细胞明显肿胀、细胞排列紊乱。免疫组化结果：脑缺血模型组小鼠海马内NeuN阳性神经元数量（93.40±10.44）较对照组（156.20±24.16）显著减少（t=2.39，P=0.04）；而APP-阳性神经元（t=2.35，P=0.047）、Aβ40-阳性神经元（t=2.54，P=0.04）以及Aβ42-阳性神经元（t=2.476，P=0.04）较假手术组明显增加。结论：本实验新建立的改良双侧颈总动脉狭窄术能导致小鼠慢性脑缺血；慢性脑缺血可加速APP/PS1双转基因AD模型小鼠的病理进程。

Abstract:

Objective：To explore the effect of chronic cerebral ischemia on the behavioral and brain morphology changes in the APP/PS1 double transgenic Alzheimer’s disease（AD） model mice. Methods：Totally 20 three-month-old APP/PS1 AD mice randomly di－vided into model group（n=10） and control group（n=10）. APP/PS1 double transgenic mice in model group were subjected to modified chronic cerebral hypoperfusion with bilateral common carotid artery permanent ligation. Morris water maze test，histologic and immuno－histochemistry were used to detect the changes of spatial learning and memory，the hippocampal morphology changes and the expres－sions of NeuN，APP，Aβ40 and Aβ42 in the brain of APP/PS1 double transgenic mice with one-month chronic cerebral ischemia and its control counterparts. Results：Behavioral experimental results：（1）There was no significant difference between two groups in the es－cape latency and path in the visible platform tests. （2）The escape latency was significantly longer in model group than in control group in the hidden platform tests. （3）The number of passing times was significantly lower in model group than in control group. HE stain－ing showed obvious swelling of neuron in the hippocampus and disordered cell arrangement in model group. Immunohistochemistry showed that the number of neuron was significantly lower in model mice group than in control group. Expressions of NeuN were signifi－cantly lower in model group than in control group. Expressions of APP，Aβ40 and Aβ42 were significantly higher in model group than in control group. Conclusion：A new modified bilateral carotid artery permanent ligation is established，which can lead to chronic cerebral ischemia. Chronic cerebral ischemia may ac－celerate the pathological progression of APP/PS1 double trans－genic AD mice.