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A production of animal model for neurofibrillary tangles of Alzheimer's disease

阿尔茨海默病神经原纤维缠结动物模型的制作

基本信息

批准号：
08680806
负责人：
SHIN Ryoung-Woon
金额：
$ 1.54万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08680806/
关键词：
Alzheimer's disease neurofibrillary tangles tau PHFtau tau蛋白 PHFtau タウ蛋白トランスジェニック

项目摘要

A production of animal model for neurofibriallay tangles of Alzheimer's diseaseNeurofibrillary tangles (NFTs) are one of the main pathological lesions of the brains affected with Alzheimer's disease (AD) and are considered to be closely associated with neuronal loss and its clinical manifestation dementia.The mechanisms involved in the formation and deposition of highly phosphorylated tau (PHFtau) which constitutes NETs should therefor be clarified for the insights into the pathogenesis of AD.In this study we aimed at producing transgenic mice which overexpress human tau as an animal model for AD NFTs. A construct in which cDNA of human tau and that for tau protein kinase I linked in tandem by CITE DNA were placed under the control of CMV-IE enhancer/beta-actin promoter was used to generate the transgenic mice. In these transgenic mice Nothern blot and immunohistochemistry revealed that the expression of human tau was at the same level or under the level of endogenous mouse tau. The construct used proved not suitable for the overexpression of tau in the CNS of the transgenic mice. We then turned to use mouse prion gene promoter, which was shown to overexptess transgene for human prion. This time we put a target for human presenilin 1, arecently identified gene associated with familial Alzheimer's disease. Using a construct in which cDNA of human presenilin 1 was placed under the control of the mouse prion gene promoter we succeeded in making transgenic mice which overexpress human PS1.Based on this system we will produce transgenic mice which overexpress human tau as the animal model of AD NFTs.

阿尔茨海默病神经纤维缠结动物模型的建立神经纤维缠结（NFTs）是阿尔茨海默病（AD）脑内的主要病理改变之一，被认为与神经元丢失及其临床表现痴呆密切相关，其机制涉及高度磷酸化的tau蛋白（PHFtau）的形成和沉积。在这项研究中，我们的目的是产生过表达人类tau蛋白的转基因小鼠作为AD NFT的动物模型。将通过CITE DNA串联连接的人tau和tau蛋白激酶I的cDNA置于CMV-IE增强子/β-肌动蛋白启动子控制下的构建体用于产生转基因小鼠。在这些转基因小鼠中，Nothingblot和免疫组织化学显示人tau蛋白的表达与内源性小鼠tau蛋白的表达水平相同或低于内源性小鼠tau蛋白的表达水平。所使用的构建体证明不适合在转基因小鼠的CNS中过表达tau。然后，我们转而使用小鼠朊病毒基因启动子，该启动子显示出对人朊病毒的过度表达转基因。这一次，我们把目标放在了人类早老素1上，这是一个最近发现的与家族性阿尔茨海默病相关的基因。我们成功地构建了人早老素1（PS1）基因的cDNA受小鼠朊蛋白基因启动子调控的转基因小鼠，并以此为基础建立了人tau蛋白基因的转基因小鼠模型。