Analysis of the APP signaling that is mediated by y-secretase.

• Project/Area Number: 17500251
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Shinshu University
• Principal Investigator: NAKAYAMA Kohzo Shinshu University, School of Medicine, Lecture, 医学部, 講師 (70192680)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2006: ¥1,100,000 (Direct Cost: ¥1,100,000); Fiscal Year 2005: ¥2,400,000 (Direct Cost: ¥2,400,000)
• Keywords: brain, nerve / brain disease / development, differentiation / dementia / aging

Research Abstract

We have shown that membrane protein Delta is cleaved by y-secretase and the intracellular domain of Delta (Dll1IC) is released from the cell membrane. Released Dll1IC translocates to nucleus and mediates transcription. Recently, it become clear that many single-transmembrane-spanning proteins including APP and Delta are substrate for γ-secretase and release intracellular domains of these protein from cell membrane. Therefore, common enzymes modulates proteolysis and release of possible signaling molecules from cell membrane have led to attractive speculation that similar mechanisms may ubiquitously contribute to y-secretase-regulated signaling pathway including APP signaling leading to Alzheimer's disease (AD).
Based on these ideas, we got results as followed :
(1) Over expression of APPIC strongly induced apoptosis.
(2) E2F1 was identified as transcription factor that bound to APPIC.
(3) Abnormally strong expressions of E2F1 ware detected in AD brains.
These results suggest that APPIC play a role through binding to E2F1 for the onset of AD.

Research Products

• [Journal Article] The Delta intracellular domain mediates TGF-β/Activin signaling through binding to Smads and has an important bi-directional function in the Notch-Delta signaling pathway (2007)
  • Author(s): Hiratochi Masahiro
  • Journal Title: Nucleic Acids Research 35 Pages: 912-922
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The Delta intracellular domain mediates TGF-β/Activin signaling through binding to Smads and has an important bi-directional function in the Notch-Delta signaling pathway (2007)
  • Author(s): Hiratochi M., Nagase H., Kuramochi Y., Koh C.S., Ohkawara T., Nakayama K
  • Journal Title: Nucleic Acids Research 35 Pages: 912-922
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] 脱髄疾患モデルと細胞治療-特に神経幹細胞移植療法について (2006)
  • Author(s): 高昌星
  • Journal Title: 神経研究の進歩 50 Pages: 525-537
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Interaction of LDL receptor-related protein 4 (LRP4) with postsynaptic scaffold proteins via its C-terminal PDZ domain-binding motif, and its regulation by Ca2+/calmodulin-dependent protein kinase II. (2006)
  • Author(s): Tian B.Q.
  • Journal Title: Eur.J.Neurosci. 11 Pages: 2864-2876
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Interaction of LDL receptor-related protein 4 (LRP4) with postsynaptic scaffold proteins via its C-terminal PDZ domain-binding motif, and its regulation by Ca2+/calmodulin-dependent protein kinase II (2006)
  • Author(s): Tian B.Q., Suzuki T., Yamauchi T., Sakagami H., Yoshimura Y., Miyazawa S., Nakayama K., Saitoh F., Zhang J., Lu Y., Kondo H., Endo S
  • Journal Title: Eur. J. Neurosci. 11 Pages: 2864-2876
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Interaction of LDL receptor-related protein 4 (LRP4) with postsynaptic scaffold proteins via its C-terminal PDZ domain-binding motif, and its regulation by Ca2+/calmodulin-dependent protein kinase II (2006)
  • Author(s): Qing-Bao Tiana^*, Tatsuo Suzukia^*‡, Takashi Yamauchi, Hiroyuki Sakagamic, Yoshiyuki Yoshimurab, Shoko Miyazawaa, Kohzo Nakayama, Fuminori Saitoha, d, Jing-Ping Zhanga, e, Yonghao Lua, Hisatake Kondoc, Shogo Endo
  • Journal Title: European Journal of Neuroscience 印刷中