2001 Fiscal Year Final Research Report Summary
DEVELOPMENT OF NOVEL β-AMYLOID GENERATION SYSTEM AND ITS APPLIMENT FOR DRUG SCREENING
| 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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| Keywords | ALZHEIMER'S DISEASE / β-AMYLOID / APP / NF-κB / Presenilin |
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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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Research Products
(24 results)
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[Publications] Tomita, S., Ozaki, T., Taru, H., Oguchi, S., Takeda, S., Yagi, Y., Sakiyama, S., Kirino, Y., Suzuki T.: "Interaction of a neuron-specific protein containing PDZ domains with Alzheimer's amyloid precursor protein"J. Biol. Chem.. 274. 2243-2254
Description
「研究成果報告書概要(欧文)」より
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[Publications] Watanabe, T., Sukegawa, J., Sukegawa, I., Tomita, S., Iijima, K., Oguchi, S., Suzuki, T., Nairn, A, C., Greengard, P.: "A 127 kDa protein (UV-DDB) binds to the cytoplasmic domain of the Alzheimer's amyloid protein precursor"J. Neurochem.. 72. 549-556
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「研究成果報告書概要(欧文)」より
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[Publications] Isohara, T., Horiuchi, A., Watanabe, T., Ando K., Czernik, A. J., Uno, I., Greengard, P. Nairn, A. C., Suzuki, T.: "Phosphorylation of the cytoplasmic domain of Alzheimer's β-amyloid precursor protein at Ser655 by a novel protein kinase"Biochem. Biophys. Res. Commun.. 258. 300-305
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「研究成果報告書概要(欧文)」より
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[Publications] Ando, K., Oishi, M. Takeda, S., Iijima, K., Isohara, T., Nairn, A., Kirino, Y., Greengard, P., Suzuki, T.: "Role of phosphorylation of Alzheimer's amyloid precursor protein during neuronal differentiation"J. Neurosci.. 19. 4421-4427
Description
「研究成果報告書概要(欧文)」より
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[Publications] Iijima, K., Ando, K., Takeda, S., Satoh, Y., Seki, T., Greengard, P., Kirino, Y., Nairn, A. C., Suzuki, T.: "Neuron-specific phosphorytlation of Alzheimer's β-amyloid precusor protein by cyclin-dependent kinase 5"J. Neurochem.. 75. 1085-1091
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「研究成果報告書概要(欧文)」より
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[Publications] Nakaya, T., Kawahara, S., Watanabe, S. Lee, D-S., Suzuki, T., Kirino, Y.: "Expression and function of a novel gene in odor-taste associative learning in the terrestrial slug"Genes Cells. 6. 43-56
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「研究成果報告書概要(欧文)」より
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[Publications] Satoh, Y., Hirakura, Y., Shibayama, S., Hirashima, N., Suzuki, T., Kirino, Y.: "β-amyloid peptides inhibit acetylcholine release from cholinergic presynaptic nerve endings isolated from an electric ray"Neurosci. Lett.. 302. 97-100
Description
「研究成果報告書概要(欧文)」より
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[Publications] Sai, X., Kawamura, Y., Kokame, K., Yamaguchi, H., Shiraishi, H., Suzuki, R., Suzuki, T., Kawaichi, M., Miyata, T., Kitamura, T., De Stropper, B., Yanagisawa, K., Komano, H.: "Endoplasmic reticulum stress-inducible protein, Herp, enhances presenilin-mediated generation of amyloid β-protein"J. Biol. Chem.. (in press).
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「研究成果報告書概要(欧文)」より
