2005 Fiscal Year Final Research Report Summary
Measurement of novel Nβ species level as a substitute for Aβ species.
| Project/Area Number |
16591135
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Psychiatric science
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| Research Institution | Osaka University |
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Principal Investigator |
OKOCHI Masayasu Osaka University, Graduate School of Medicine, Assistant, 医学系研究科, 助手 (90335357)
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| Co-Investigator(Kenkyū-buntansha) |
TAGAMI Shinji Osaka University, Graduate School of Medicine, Assistant, 医学系研究科, 助手 (40362735)
TAKEDA Masatoshi Osaka University, Graduate School of Medicine, Professor, 医学系研究科, 教授 (00179649)
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| Project Period (FY) |
2004 – 2005
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| Keywords | Alzheimer's disease / presenilin / γ-secretase / Notch signaling / Amyloid-β peptide / βAPP / Notch-1 / γ-cleavage |
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| Research Abstract |
The canonical pathway of Notch signaling is mediated by regulated intramembrane proteolysis (RIP). In the pathway, ligand binding results in sequential proteolysis of the Notch receptor, and presenilin (PS)-dependent intramembrane proteolysis at the interface between the membrane and cytosol liberates the Notch-1 intracellular domain (NICD), a transcription modifier. Because the degradation of the Notch-1 transmembrane domain is thought to require an additional cleavage near the middle of the transmembrane domain, extracellular small peptides (Notch-1 Abeta-like peptide (Nbeta)) should be produced. Here we showed that Nbeta species are indeed secreted during the process of Notch signaling. We identified mainly two distinct molecular species of novel Nbeta, Nbeta21 and C-terminally elongated Nbeta25, which were produced in an approximately 5:1 ratio. This process is reminiscent of the production of Alzheimer disease-associated Abeta. PS pathogenic mutants increased the production of the longer species of Abeta (Abeta42) from beta-amyloid protein precursor. We revealed that several Alzheimer disease mutants also cause a parallel increase in the secretion of the longer form of Nbeta. Strikingly, chemicals that modify the Abeta42 level caused parallel changes in the Nbeta25 level. These results demonstrated that the characteristics of C-terminal elongation of Nbeta and Abeta are almost identical. In addition, because many other type 1 membrane-bound receptors release intracellular domains by PS-dependent intramembrane proteolysis, we suspect that the release of Abeta-or Nbeta-like peptides is a common feature of the proteolysis during RIP signaling. We anticipate that this study will open the door to searches for markers of RIP signaling and surrogate markers for Abeta42 production.
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[Journal Article] Presenilin-dependent γ-secretase on plasma membrane and endosomes is functionally distinct.2006
Author(s)
Fukumori A, Okochi M, Tagami S, Jiang J, Itoh N, Nakayama T, Yanagida K, Ishizuka-Katsura Y, Morihara T, Kamino K, Tanaka T, Kudo T, Tanii H, Ikuta A, Haass C, Takeda M.
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Journal Title
Biochemistry 45/15
Pages: 4907-14
Description
「研究成果報告書概要(和文)」より
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[Journal Article] Development of new screening system for Alzheimer disease, in vitro A・ sink assay, to identify the dissociation of soluble A・ from fibrils2006
Author(s)
Sato N, Okochi M, Taniyama Y, Kurinami H, Shimamura M, Takeuchi D, Hamada H, Fukumori A, Kiyosue K, Taguchi T, Tanaka T, Miyasaka M, Takeda M, Ogihara T, Morishita R
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Journal Title
Neurobiol Dis 22/3
Pages: 487-95
Description
「研究成果報告書概要(和文)」より
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[Journal Article] Presenilin-dependent gamma-secretase on plasma membrane and endosomes is functionally distinct.2006
Author(s)
Fukumori A, *Okochi M, Tagami S, Jiang J, Itoh N, Nakayama T, Yanagida K, Ishizuka-Katsura Y, Morihara T, Kamino K, Tanaka T, Kudo T, Tanii H, Ikuta A, Haass C, Takeda M.
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Journal Title
Biochemistry 18;45(15)
Pages: 4907-14
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Development of new screening system for Alzheimer disease, in vitro Abeta sink assay, to identify the dissociation of soluble Abeta from fibrils.2006
Author(s)
Sato N, Okochi M, Taniyama Y, Kurinami H, Shimamura M, Takeuchi D, Hamada H, Fukumori A, Kiyosue K, Taguchi T, Tanaka T, Miyasaka M, Takeda M, Ogihara T, Morishita R.
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Journal Title
Neurobiol Dis 22(3)
Pages: 487-95
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Alzheimer's γ-secretase mechanism produces Amyloid-β-protein like peptides simultaneously with release of intracellular signaling fragments.2004
Author(s)
Okochi.M., Fukumori, A., Satoh, Y., Aidaralieva, N., Tanii, H., Kamino, K., Tanaka, T., Kudo, T., Takeda M.
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Journal Title
Molecular Neurobiology of Alzheimer Disease and Related Disorders)(Karger Press)
Pages: 31-41
Description
「研究成果報告書概要(欧文)」より
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[Book] Molecular Neurobiology of Alzheimer Disease and Related Disorders "Alzheimer's γ-secretase mechanism produces Amyloid-β-protein like peptides simultaneously with release of intracellular signaling fragments"2004
Author(s)
Okochi, M., Fukumori, A., Satoh, Y., Aidaralieva, N., Tanii, H., Kamino, K., Tanaka, T., Kudo, T., Takeda M.
Total Pages
31-41
Publisher
Karger Press
Description
「研究成果報告書概要(和文)」より
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