PRESENILIN 1 TRANSGENIC MICE--ALZHEIMER DISEASE MODELS

对某些基础突变的理解的最新进展 家族性阿尔茨海默病(AD)开辟了治疗阿尔茨海默病的新途径 为此开发合适的小动物模型 神经退行性疾病。阿尔茨海默病遗传基因座的特征 在第14和1号染色体上发现了两个高度相关的 蛋白质，早老素-1(PS-1)和早老素-2(PS-2)，其中 在一些家系中，突变与早发性AD有关。私家侦探。 已经成功培育出了表达各种形式的转基因小鼠 PS-1(包括突变型和野生型蛋白)在 血小板衍生生长因子B链启动子。这些老鼠 代表了对由以下原因引起的早发性AD进行建模的尝试 并评估两者过度表达的后果 这些蛋白质的野生型和突变型。一个主要的标准是 这些动物可以被评估为适合AD的模型 转基因是否会导致类似AD的病理发现。 因此，这个项目的第一个具体目标是调查 多种形式的血管紧张素转换酶过度表达的神经病理后果 在这些转基因小鼠的大脑中发现了PS-1。 这些小鼠也有可能成为神经元的来源。 用于细胞培养实验的组织。这样的实验可以 阐明这些形式的PS-1对细胞的影响 发挥作用并对各种外部影响作出反应。 然而，首先关键的是确定在组织培养过程中， 以及转基因基因在大脑的哪些区域是活跃的。 因此，这个项目的第二个具体目标是描述 PS-1转基因在不同来源神经细胞原代培养中的表达 这些动物的大脑区域。 这些实验的综合结果将是表征 这些动物在完整的大脑水平上，并作为潜在的来源 培养的原代神经元。通过对该模型的详细分析 用于AD的系统在这两个级别上都可以使用 这是一个评估可能的治疗效果的系统 对这种毁灭性的神经退行性疾病的干预。

Recent advances in the understanding of certain mutations which underlie familial Alzheimer disease (AD) have opened new approaches to the development of appropriate small animal models for this neurodegenerative disorder. The characterization of the AD genetic loci on chromosomes 14 and 1 has led to the discovery of two highly related proteins, presenilin-1 (PS-1) and presenilin-2 (PS-2), in which numerous mutations have been linked to early-onset AD in some families. The P.I. has successfully generated transgenic mice which express various forms of PS-1 (including mutant and wild type proteins) under the control of the platelet-derived growth factor B-chain promotor. These mice represent an attempt to model the early-onset AD caused by these mutations and to assess the consequences of the over-expression of both wild type and mutant forms of these proteins. One major criterion by which these animals can be evaluated as an adequate model for AD is whether the transgene leads to AD-like pathologic findings. Thus, the first Specific Aim of this project is to investigate the neuropathologic consequences of the over-expression of various forms of PS-1 in the brains of these transgenic mice. These mice also have the potential to serve as a source of neuronal tissue for use in cell culture experiments. Such experiments can elucidate the consequences of these forms of PS-1 on cellular functioning and in response to a wide variety of exogenous influences. It is first critical, however, to determine when, during tissue culture, and from which brain regions the transgene is active. Thus, the second Specific Aim of this project is to characterize the expression of PS-1 transgenes in primary neuronal cultures of various brain regions from these animals. The combined outcome of these experiments will be the characterization of these animals at the intact brain level and as a potential source for cultured primary neurons. Through the detailed analysis of this model system for AD at both of these levels, it may become possible to use this a system to evaluate the effects of possible therapeutic interventions for this devastating neurodegenerative disorder.