TRANSGENIC MODELS OF FAMILIAL ALZHEIMER'S DISEASE

常染色体显性遗传性家族性阿尔茨海默病(FAD)与 编码淀粉样前体蛋白(APP)和两个 具有7-9个跨膜结构域的相关蛋白(PS1/PS2)。使用 最近开发的表达载体，我们建议创建表达 相对较高的野生型(Wt)水平(低于内源的4倍)和 突变体PS1/PS2，并确定神经生物学/神经病理性 这些动物的表型。此外，作为正在进行的努力的一部分 利用cDNA和酵母菌人工构建APP连锁FAD模型 染色体/胚胎干细胞的方法，我们已经产生了一些小鼠 表达wt和人APP的线条；wt和突变体的影响 APP生物学上的PS1/PS2可以在同时携带两者的小鼠身上进行检测 转基因。有几条证据有力地鼓励我们这样做 努力：表达载体驱动APP和PS1的表达 以一种相对依赖复制的方式；使用这些方法，我们有 已生成的含有PS1-wt和PS1-A246E基因的创建者 和PS1核酸探针，以及抗体已经证明我们的 转基因构建物在相对较高水平表达wt和突变体PS1 (大约是内源的5倍)。我们预计高表达的小鼠 突变型PS1/PS2水平将发展为行为/大脑异常 与FAD分享功能。此外，通过育种范例，品系 APP转基因小鼠或空白小鼠可用于探讨 PS1/PS2和APP在疾病发病机制中的作用我们有信心 这些努力将导致FAD转基因模型的开发，即 对它的研究将阐明疾病的机制。此外，因为 我们计划让这些动物广泛使用，这样它们就可以被 其他研究人员将测试治疗阿尔茨海默病的新疗法。

Autosomal dominant familial Alzheimer's disease (FAD) has been linked to mutations in genes that encode amyloid precursor proteins (APP) and two related proteins (PS1/PS2) with 7-9 transmembrane domains. Using a recently developed expression plasmid, we propose to create mice expressing relatively high level (less than 4 times endogenous) of wild-type (wt) and mutant PS1/PS2, and to determine the neurobiological/neuropathical phenotypes of these animals. Moreover, as part of an ongoing effort to generate models of APP-linked FAD using cDNA and yeast artificial chromosome/embryonic stem cell methods, we have produced a number of mouse lines that expressing wt and human APP; the influences of wt and mutant Ps1/PS2 on the biology of APP can be examined in mice harboring both transgenes. Several lines of evidence strongly encourage us in this effort: the expression plasmid vector drives the expression of APP and PS1 in a relatively copy-dependent manner; and using these approaches, we have already generated founders harboring PS1-wt and PS1-A246E cDNA transgenes and PS1 nucleic acid probes, and antibodies have demonstrated that our transgene construct expresses wt and mutant PS1 at relatively high levels (about 5 fold over endogenous). We anticipate that mice expressing high levels of mutant PS1/PS2 will develop behavioral/brain abnormalities that share features with FAD. Moreover, through breeding paradigms, lines of APP transgenic or null mice can be used to explore the interactions of PS1/PS2 and APP in the pathogenesis of disease. We are confident that these efforts will lead to development of transgenic models of FAD, the study of which will clarify the mechanisms of disease. Moreover because we plan to make these animals widely available so that they can be used by other investigators to test novel therapies for AD.