TRANSGENIC MOUSE MODEL ALZHEIMER'S DISEASE AMYLOIDOSIS

这项研究计划的目标是确定淀粉样蛋白的作用 老年痴呆症的病因中的斑块形成。 为了能够 研究潜在的机制，并检查β- 淀粉样蛋白沉积，我们正在开发一个小动物模型， 病理事件 已经产生了转基因小鼠， 细胞外β-淀粉样蛋白免疫反应沉积在他们的大脑。 这些 沉积物在形态上类似于几种β-淀粉样蛋白免疫反应性 阿尔茨海默病患者大脑中的结构。 一 研究目的是进一步表征这些转基因小鼠， 他们的组织病理学与人类的情况相似。 可能的年龄- β-淀粉样蛋白沉积，细胞骨架改变， 神经递质系统的异常，神经细胞的损失将是 用免疫细胞化学研究。 研究的另一个目的是 是通过产生新的β-淀粉样蛋白， 转基因小鼠 这些新的转基因小鼠将被编程来表达 外源性β-淀粉样蛋白前体基因类似于那些用来产生 β-淀粉样蛋白形成的表型-特异性编码序列除外 改变。 表达突变的β-淀粉样蛋白前体基因的小鼠 将再次评估β-淀粉样蛋白沉积， 免疫细胞化学 新的转基因小鼠的表型 应进一步确定β-淀粉样蛋白前体的特定结构域 参与淀粉样蛋白的形成。 老鼠的发育 阿尔茨海默病淀粉样变模型的建立及其机制的阐明 淀粉样蛋白形成的机制可能有助于鉴定新的 设计用于预防β-淀粉样蛋白形成的治疗剂 患有这种疾病的人。

The goal of this research program is to determine the role of amyloid plaque formation in the etiology of Alzheimer's disease. To be able to study the underlying mechanism(s) and to examine the consequences of beta- amyloid deposition, we are developing a small animal model of this pathological event. Transgenic mice have been generated which display extracellular beta-amyloid immunoreactive deposits in their brains. These deposits morphologically resemble several beta-amyloid immunoreactive structures observed in the brains of Alzheimer's disease victims. One research objective is to further characterize these transgenic mice as to similarity of their histopathology to the human condition. Possible age- dependent occurrence of beta-amyloid deposits, cytoskeletal alterations, abnormalities of neurotransmitter systems, and neuronal cell loss will be investigated using immunocytochemistry. Another objective of the research is to determine the mechanism of beta-amyloid formation by producing new transgenic mice. These new transgenic mice will be programmed to express exogenous beta-amyloid precursor genes similar to those used to produce the phenotype of beta-amyloid formation - except for specific coding sequence alterations. The mice expressing the mutated beta-amyloid precursor genes will be evaluated for beta-amyloid deposits again using immunocytochemistry. The resulting phenotypes of the new transgenic mice should further define the specific domains of the beta-amyloid precursor which are involved in amyloid formation. Both the development of a mouse model of Alzheimer's disease amyloidosis and the elucidation of the mechanism of amyloid formation may be useful in the identification of novel therapeutic agents designed to prevent beta-amyloid formation in individuals with this disease.