Measurement of novel Nβ species level as a substitute for Aβ species.

• Project/Area Number: 16591135
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Osaka University
• Principal Investigator: OKOCHI Masayasu Osaka University, Graduate School of Medicine, Assistant, 医学系研究科, 助手 (90335357)
• 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)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,400,000 (Direct Cost: ¥3,400,000); Fiscal Year 2005: ¥1,600,000 (Direct Cost: ¥1,600,000); Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
• Keywords: Alzheimer's disease / presenilin / γ-secretase / Notch signaling / Amyloid-β peptide / βAPP / Notch-1 / γ-cleavage

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.

Research Products

• [Journal Article] Secretion of the Notch-1 Aβ-like peptide during Notch signaling. (2006)
  • Author(s): Okochi M, Fukumori A, Jiang J, Itoh N, Kimura R, Steiner H, Haass C, Tagami S, Takeda M.
  • Journal Title: J Biol Chem. 281/12 Pages: 7890-8
  • Description: 「研究成果報告書概要(和文)」より
• [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.
  • Journal Title: Biochemistry 45/15 Pages: 4907-14
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The GxGD motif of presenilin contributes to catalytic function and substrate identification of γ-secretase. (2006)
  • Author(s): Yamasaki A, Eimer S, Okochi M, Smialowska A, Kaether C, Baumeister R, Haass C, Steiner H
  • Journal Title: J Neurosci 26/14 Pages: 3821-8
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Development of new screening system for Alzheimer disease, in vitro A・ sink assay, to identify the dissociation of soluble A・ 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
  • Journal Title: Neurobiol Dis 22/3 Pages: 487-95
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Secretion of the Notch-1 Aβ-like peptide during Notch signaling. (2006)
  • Author(s): Okochi M, Fukumori A, Jiang J, Itoh N, Kimura R, Steiner H, Haass C, Tagami S, Takeda M.
  • Journal Title: J Biol Chem 24;281(12) Pages: 7890-8
  • Description: 「研究成果報告書概要(欧文)」より
• [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.
  • Journal Title: Biochemistry 18;45(15) Pages: 4907-14
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Steiner The GxGD motif of presenilin contributes to catalytic function and substrate identification of gamma-secretase. (2006)
  • Author(s): Yamasaki A, Eimer S, Okochi M, Smialowska A, Kaether C, Baumeister R, Haass C
  • Journal Title: J Neurosci 5;26(14) Pages: 3821-8
  • Description: 「研究成果報告書概要(欧文)」より
• [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.
  • Journal Title: Neurobiol Dis 22(3) Pages: 487-95
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Secretion of the Notch-1 Aβ-like peptide during Notch signaling. (2006)
  • Author(s): Okochi M, Fukumori A, Jiang J, Itoh N, Kimura R, Steiner H, Haass C, Tagami S, Takeda M.
  • Journal Title: J Biol Chem. 3月号予定(in press)
• [Journal Article] Development of new screening system for Alzheimer disease, in vitro Aβ sink assay, to identify the dissociation of soluble Aβ 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
  • Journal Title: Neurobiology of Disease. 3月号予定(in press)
• [Journal Article] The protease active site domain of γ-secretase contributes to substrate identification (2006)
  • Author(s): Yamasaki A, Eimer S, Okochi M, Smialowska A, Kaether C, Baumeister R, Haass C, Steiner HH
  • Journal Title: J Neuroscience 3月号予定(in press)
• [Journal Article] 非ステロイド性消炎薬(NSAIDs)のAβ42産生阻害作用とその応用 (2006)
  • Author(s): 大河内正康, 田上真次, 武田雅俊
  • Journal Title: CURRENT THERAPY 3月号予定(印刷中)
• [Journal Article] Possible assessment of Alzheimer's γ-secretase activity by level of Aβ-like peptides (2004)
  • Author(s): Okochi, M., Takeda, M.
  • Journal Title: Psychogeriatrics 4 Pages: 23-27
  • NAID: 10018089800
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Possible assessment of Alzheimer's y-secretase activity by level of Aβ-like peptides (2004)
  • Author(s): Okochi M, Takeda, M.
  • Journal Title: Psychogeriatrics 4 Pages: 23-27
  • Description: 「研究成果報告書概要(欧文)」より
• [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.
  • 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
• [Book] アルツハイマー病 : 治療の可能性を探る「アミロイドβタンパク質産生の異常がアルツハイマー病につながる」 (2005)
  • Author(s): 大河内正康
  • Publisher: クバプロ
  • Description: 「研究成果報告書概要(和文)」より
• [Book] アルツハイマー病:治療の可能性を探る 2005 第19回「大学と科学」公開シンポジウム講演抄録集(単行本) (2005)
  • Author(s): 大河内正康
• [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.
  • Publisher: Karger Press
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 日本医師会雑誌131巻、第12号、特別号 精神障害の臨床 アルツハイマー病の分子病態 (2004)
  • Author(s): 大河内正康, 武田雅俊
  • Publisher: 日本医師会
• [Book] Molecular Newrobiology 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., et al.
  • Publisher: Karger Press
• [Book] 日本臨床62巻 増刊号1,痴呆症侯学(2)臨床編 アミロイド前駆体蛋白遺伝子変異によるアルツハイマー病 (2004)
  • Author(s): 大河内正康, 武田雅俊
  • Publisher: 日本臨床
• [Book] Molecular Medicine 41 Aβの毒性発現機構 (2004)
  • Author(s): 大河内正康, 田上真次, 武田雅俊
  • Publisher: 中山書店
• [Book] Psychiatry Today, No.4 アルツハイマー病の診断バイオマーカーの新たなコンセプト:Aβ様ペプチド (2004)
  • Author(s): Okochi, M.
  • Publisher: 中山書店
• [Patent(Industrial Property Rights)] 特許出願(セル・フリー・Notch切断分析方法および薬剤スクリーニング方法) (2004)
  • Inventor(s): 大河内正康, 武田雅俊
  • Industrial Property Rights Holder: 大河内正康, 武田雅俊, 大阪TLO
  • Filing Date: 2004-11-10
  • Description: 「研究成果報告書概要(和文)」より
• [Patent(Industrial Property Rights)] セル・フリー・Notch切断分析方法および薬剤スクリーニング方法 (2004)
  • Inventor(s): 大河内正康, 武田雅俊
  • Industrial Property Rights Holder: 大阪TLO
  • Filing Date: 2004-11-10