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Secretion of amyloid precursor protein via signal transduction pathway

通过信号转导途径分泌淀粉样前体蛋白

基本信息

批准号：
06454705
负责人：
ISHIURA Shoichi
金额：
$ 4.03万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06454705/
关键词：
Alzheimer's disease Amyloid Signal transduction C kinase Secretion アミロイドβ蛋白質

项目摘要

Alzheimer's disease (AD) is characterized by progressive neurodegeneration. One of the features of AD is the formation of senile plaques, which contain mainly beta protein, small peptides comprising 39-43 amino acid residues, processed from a large membrane-bound amyloid precursor protein (APP). In AD brain, APP is converted to beta protein by abnormal processing, while almost all APP is normally secreted following cleavage of the precursor at amino acid 16 which falls within the beta protein molecule. This scission also leads to the retention of the residual C-terminal non-amyloidogenic 10 kDa fragment within the membrane. The regulation of beta protein formation by aberrant processing or of a secreted form by constitutive processing from the intact APP molecule remains unclear.In order to study the mechanism of intracellular sorting and processing of the APP,we deleted two potential N-linked glycosylation sites, G-protein binding site, endosome-retension signal and lysosome-targeting signal of APP by site-directed mutagenesis. Wild-type and mutant APPs were expressed in COS-1 cells by cDNA transfection and the expression of the protein products and secretion of N-terminal large fragment was observed. The initial secretion of the mutant APP appeared to be slow compared with wild type.The amount of APP secreted from PKC-transfected cells was higher than those from untransfected. These results suggest that PKC regulates the secretion of APP through a signaling pathway.

阿尔茨海默病（Alzheimer's disease，AD）是一种以进行性神经退行性变为特征的疾病。AD的特征之一是老年斑的形成，其主要含有β蛋白，即由大的膜结合淀粉样前体蛋白（APP）加工而成的包含39-43个氨基酸残基的小肽。在AD脑中，APP通过异常加工转化为β蛋白，而几乎所有APP在前体在福尔斯位于β蛋白分子内的氨基酸16处裂解后正常分泌。这种断裂也导致残留的C-末端非淀粉样蛋白生成的10 kDa片段保留在膜内。为了研究APP的细胞内分选和加工机制，我们采用定点突变的方法，删除了APP的两个潜在的N-糖基化位点、G-蛋白结合位点、内体滞留信号和溶酶体靶向信号。通过cDNA转染方法在COS-1细胞中表达野生型和突变型APPs，观察蛋白产物的表达和N端大片段的分泌。与野生型相比，突变型APP的初始分泌速度较慢，转染PKC的细胞分泌APP的量高于未转染的细胞。这些结果表明，PKC通过信号通路调节APP的分泌。