| Project/Area Number |
11557179
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Biological pharmacy
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| Research Institution | HOKKAIDO UNIVERSITY (2001)
The University of Tokyo (1999-2000) |
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Principal Investigator |
SUZUKI Toshiharu HOKKAIDO UNIV. GRADUATE SCH. OF PHARMACEUTICAL SCI., 大学院・薬学研究科, 教授 (80179233)
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| Co-Investigator(Kenkyū-buntansha) |
MARUMOTO Yasumasa DAIICHI PHARMACEUTICAL CO., LTD, NEW PRODUCT RESEARCH LABORATORIES III, 創薬第3研究所, 研究員
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| Project Period (FY) |
1999 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥13,400,000 (Direct Cost: ¥13,400,000)
Fiscal Year 2001: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2000: ¥4,700,000 (Direct Cost: ¥4,700,000)
Fiscal Year 1999: ¥4,700,000 (Direct Cost: ¥4,700,000)
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| Keywords | ALZHEIMER'S DISEASE / β-AMYLOID / APP / NF-κB / Presenilin / NF-κB / GeneChip |
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| Research Abstract |
In Alzheimer's disease (AD), the β-amyloid peptide (Aβ) is thought to be produced as a results of the aberrant metabolism of APP. APP cytoplasmic domain contains a novel and important signal for APP metabolism. A single amino acid mutation that changed arginine at amino acid 672 of APP695 to a non-basic amino acid greatly increase the production of intracellular CTFβ, but do not results in increased secretion of Aβ. Further expression of presenilin (PS1) cleaved CTFβ at γ-site and results in great amount of Aβ generation. This cellular system can separate γ-cleavage of CTFβ from prior β-cleaving reaction, and indicated that the APP metabolism differs from normal metabolic pathway in which γ-cleavage occurs just after β-cleavage. Using this cell system, it is possible to screen compounds that suppress Aβ production. We further report that a transcription factor, NF-κB/p65, induces increased secretion of amyloidogenic Aβ42 but not Aβ40. The results suggest that the gene product under the expression control of NF-κB plays an important role in Aβ generation. This may be also a novel target to develop drug which suppresses Aβ generation.
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