【作者】 唐克峰；

【导师】 周江宁；

【作者基本信息】 中国科学技术大学 ， 神经生物学， 2009， 硕士

【摘要】 阿尔茨海默氏病(Alzheimer’s disease,AD)是一种与衰老相关的神经退行性疾病,是痴呆的一种主要形式,占所有痴呆病例的60%-70%。老龄是散发性AD发生的重要危险因子。载脂蛋白E(Apolipoprotein E,ApoE)对胆固醇和甘油三酸酯的代谢和分配起着重要的作用,主要在肝脏和脑的星型胶质细胞中表达。人类的载脂蛋白E基因具有多态性,有三个不同的等位基因(ε2,ε3,ε4),产生了六个不同的显型(E2/2, E2/3,E2/4,E3/3, E3/4和E4/4)。大量研究表明ApoE基因亚型与AD的发病密切相关,其中ApoE4等位基因被认为是AD患病的高风险因子。作为AD及其相关疾病的动物模型,Glial Fibrillary Acidic Protein (GFAP) -apoE转基因鼠已经被广泛地用于研究领域。但是令人惊讶的是关于GFAP-apoE转基因鼠脑形态学的基本信息非常有限.本研究的目的在于通过硫堇(Thionin)染色和苏木精-伊红(HE)染色,这两个传统的染色方法,观察在正常衰老过程中不同GFAP-apoE转基因鼠脑的大体形态学的基本特征,并特别观察了海马神经元数目和大小以及脑微血管形态学的变化。结果发现,在apoE3/3和apoE4/4型转基因鼠中,大脑皮层分层的一般形态学无差异。在不同年龄的ApoE3/3和ApoE4/4型鼠之间,海马CA1-CA3亚区的神经元数目没有明显差异性。ApoE3/3和ApoE4/4型鼠的CA1亚区细胞胞体面积随年龄的增高而降低(P<0.001)。在老年组中,ApoE4/4型鼠的细胞胞体面积小于ApoE3/3鼠(P<0.05)。三只老年ApoE4/4型鼠的丘脑都显示了不同程度微血管损伤,损伤度分别为5.24%; 1.41%;3.97%。但是在三只老年ApoE3/3型鼠中只有一只表现出微血管损伤,损伤度为0.85%。本研究提示GFAP-apoE转基因鼠海马CA1区细胞大小随着衰老而减小,但不受apoE基因型的影响。老年apoE4型鼠海马CA1区细胞萎缩要大于老年apoE型鼠;老年apoE4/4型鼠丘脑微血管损伤大于apoE3/3型鼠。上述研究结果为在转基因动物中研究apoE与AD的发病机制之间的关系提供了脑大体形态学基础。更多还原

【Abstract】 Alzheimer’s disease (AD) is a kind of age related neurodegenerative disease, a most common format of dementia, constituting 60% to 70% of all cases. Age is an important factor for onset of sporadic AD.Apolipoprotein E (ApoE) plays an important role in the distribution and metabolism of cholesterol and triglycerides. ApoE is synthesized by the liver, brain (primarily astrocytes).in humans. The ApoE gene shows polymorphism, with three different alleles (ε2,ε3,ε4), and gives rise to six different phenotypes (E2/2, E2/3, E2/4, E3/3, E3/4, E4/4). Large studies have shown that isoforms of ApoE gene is associated with onset of AD. ApoE4 allele is believed as a major genertic risk factor of AD.To our surprise, although GFAP-apoE transgenic mice have been widely used in the study of AD and other related diseases, there is limited information on the general brain morphology in the transgenic mice. In the present study, we aimed to investigate the effect of ApoE isoforms on the number and size of cells in hippocampus and the morphology of blood vessels in the brain of GFAP-apoE transgenic mice with age by the two conventional staining methods, thionin staining and HE stainging. In our results,We did not observe apparent differences in the cortical layer between apoE3/3 and apoE4/4 mice. Our results showed that the number of hippocampus cells in CA1–CA3 areas was not significantly different between apoE3/3 and apoE4/4 mice among different age groups. We observed that the size of cells in CA1 area decreased in GFAP-apoE mice with aging; in 20-21 months, this cellular atrophy in apoE4/4 mice was more significantly evident than that in apoE3/3 mice(P<0.05). In 20-21months,old apoE4 mice all showed microvascular lesion in varying degrees in thalamus, the lesion degrees were 5.24%; 1.41%; 3.97%, respectively. But there were only one of three old apoE3/3 mice, which showed microvascular lesion in thalamus, and the lesion degree was 0.85%. The current study suggests that the CA1 cellular size in hippocampus decreases with aging, which is not affected by the apoE genotype. The CA1 cell atrophy is more severe in old apoE4/4 mice as compared with age-matched apoE3/3 mice. These morphological studies will provide a basis of brain morphology for studying the relation between apoE and the mechanism of AD in GFAP-apoE transgenic mice更多还原