| Project/Area Number |
06454705
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Neuroscience in general
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| Research Institution | The University of Tokyo |
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Principal Investigator |
ISHIURA Shoichi Institute of Molecular and Cellular Biosciences, The University of Tokyo, Associate Professor, 分子細胞生物学研究所, 助教授 (10158743)
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| Co-Investigator(Kenkyū-buntansha) |
SORIMACHI Hiroyuki Institute of Molecular and Cellular Biosciences, The University of Tokyo, Assist, 分子細胞生物学研究所, 助手 (10211327)
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| Project Period (FY) |
1994 – 1995
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| Project Status |
Completed (Fiscal Year 1995)
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| Budget Amount *help |
¥6,300,000 (Direct Cost: ¥6,300,000)
Fiscal Year 1995: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 1994: ¥4,700,000 (Direct Cost: ¥4,700,000)
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| Keywords | Alzheimer's disease / Amyloid / Signal transduction / C kinase / Secretion / アミロイドβ蛋白質 |
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| Research Abstract |
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.
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