APP/PS1阿尔茨海默病转基因动物模型前联合异常改变(英文)

Anterior commissure anomalies in APP/PS1 transgenic mouse models of Alzheimer’s disease

背景:阿尔茨海默病研究大多主要集中在淀粉样β蛋白和神经元死亡之间的关系,但是对白质损害研究却鲜有报道。目的:观察APP/PS1阿尔茨海默病转基因动物模型前联合病理改变特点。设计、时间及地点:以组织学改变为依据,分组对照观察,于2007-09/2008-09在华中科技大学同济医学院附属同济医院神经科实验室完成。材料:雌性转基因APP/PS1小鼠(表达人突变的PS1(M146L)基因和APP(KM670/671NL,V717I)基因,对照组老鼠选用的是没有淀粉样蛋白沉积的雌性PS1小鼠。分为年轻组(2月龄,包括8只APP/PS1,7只PS1)和老年组(24月龄,包括6只APP/PS1,7只PS1)。方法:利用刚果红和免疫组织化学方法观测该AD转基因模型脑内淀粉样改变;采用氯化金髓鞘染色方法和轴突免疫组织化学染色,利用吸光度方法对前联合轴突密度和髓鞘化程度的染色进行相对吸光度定量分析。主要观察指标:①细胞内和细胞外淀粉样β蛋白的染色。②在冠状位前联合的平均面积大小测量。③前联合处轴突密度和髓鞘化程度定量相对吸光度值。结果:在老年组APP/PS1小鼠,大量的刚果红阳性染色出现在皮质,海马以及丘脑,前联合也出现阳性染色;细胞内淀粉样β蛋白仅出现在年轻组APP/PS1的皮质结构中。在老年组PS1组小鼠,前联合的表面积大小比年轻组PS1和老年组APP/PS1组小鼠都有显著的增长。老年组包括APP/PS1和PS1组轴突的染色都有显著的下降,髓鞘化程度比年轻组有增高趋势。不同表型分析显示,轴突密度和髓鞘化程度在年轻组APP/PS1和PS1组相当;老年APP/PS1组轴突密度比PS1组有显著的下降,老年组APP/PS1小鼠髓鞘化程度与PS1无显著差别。结论:随着年龄的增长,APP/PS1阿尔茨海默病转基因小鼠模型前联合存在着轴突的丢失,髓鞘相对保持完整。淀粉样β蛋白对轴突有直接的毒性作用。

BACKGROUND： Much research focuses on the link between 13-amyloid peptide and neuron death, but there is little work about white matter alterations in the Alzheimer＇s disease. OBJECTIVE： To investigate the anterior commissure pathological alteration in the APP/PS1 transgenic mice which model brain amyloidosis of Alzheimer＇s disease. DESIGN, TIME AND SETTING： A grouping observational study based on the histology was performed in the Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology between September 2007 and September 2008. MATERIALS： Female transgenic APP/PS1 mice [Thy1 APP751 SL （Swedish mutation KM670/671NL, London mutation V7171 introduced in human sequence APP751） × human mutation gene PS1 M146L], control animals were amyloid-deposit free female PS1 mice. A total of 28 mice were divided into young group （2 months, 8 APP/PS1, 7 PS1） and old group （24 months, 6 APP/PS1, 7 PS1）. METHODS： The slides of brain tissue were stained with Congo red and antibody against amyloid beta （4G8） to detect brain amyloidosis in Alzheimer＇s disease transgenic model. Myelin was stained with gold chloride and axon was stained with anti-neurofilament M antibody. The anterior commissure axonal density and myelination were quantitatively analyzed with the relative optical density value of staining with densitometry. MAIN OUTCOME MEASURES： ①The staining of intracellular and extracellular amyloid beta; ②the average area of anterior commissure in the coronal brain tissue sections; ③the relative optical density value of myelin and axon staining in the anterior commissure. RESULTS： A lot of Congo red positive amyloid beta plaques were observed in the cortex, hippocampus, thalamus, and anterior commissure of aged APP/PS1 mice, while intracellular amyloid beta was only present in the cortex of young APP/PS1 mice. A prominent increase in the surface area of the anterior commissure was observed in aged PS1 mice compared with young PS1 mice and aged APP/PS1 mice. The neurofilament staining remarkably decreased, both in aged APP/PS1 and aged PS1 mice; an increase trend of myelination in the anterior commissure was observed both the forementioned groups. Different phenotype analysis demonstrated that axonal density and myelination was comparative in the young APP/PS1 and young PS1 mice; axonal density of aged APP/PS1 mice decreased remarkably compared with aged PS1 control mice, while myelination of aged APP/PS1 mice had no significant difference with aged PS1 mice. CONCLUSION： There exists an axon loss in the anterior commissure in the aged APP/PS1 mice with a complete myelin sheath. The amyloid beta shows a direct toxicity on the axon.