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Study of a novel rescue factor, Humanin, for neuronal death relevant to familial Alzheimer's disease

Research Project

Project/Area Number 13670150
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Pathological medical chemistry
Research InstitutionKEIO UNIVERSITY

Principal Investigator

ARAKAWA Yoshiko  Keio University, School of Medicine, Associate Professor, 医学部, 講師 (00327496)

Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2002: ¥1,500,000 (Direct Cost: ¥1,500,000)
KeywordsHumaninn (HN) / Anti-Alzheimer's Disease factors / アルツハイマー病拮抗因子 / アルツハイマー病根治薬
Research Abstract

Humanin (HN) is a secretory peptide that inhibits neurotoxicity by various Alzheimer's disease-relevant insults. In this project, we focused on HN structure-function analysis. Followings are the findings derived from this, project.
1) HN structure in solution by CD and sedimentation analysis.
Both HN and HNG showed some secondary structure typical of anti-parallel beta-sheets in water and saline : HNG is a mutant of HN and has a 1000-fold higher activity. The structure is different between the two solvents and between HN and HNG. Sedimentation analysis showed that HN and HNG form oligomers, greater than trimers, in, Saline, but are mostly monomeric in water. The size of oligomers in saline decreases as the peptide concentration is decreased.
2) Amino acid requirement of HN essential for the function
We have identified that the substitution of Leu9 for Arg nullifies the extracellular secretion of HN. While Ala substitution of neither residue in HN sequence affected HN secretion, Arg substit … More ution revealed that the two structures -Leu9-Leu11 and Pro19-Va120 -were essential for the secretion of full-length HN. In the Leu9-Leu11 domain, the, Leu10 residue turned out to play a central role in this function, because the Asp substitution of Leu10, but not Leu9 or Leu11, nullified the secretion of HN. We also investigated a comprehensive structure-function relationship for the neuroprotective function of full-length HN, which revealed (i) that Pro3, Ser7, Cys8, Leu9, Leu12, Thr13, Ser14, and Pro19 were essential for this function and (ii) that Ser7 and Leu9 were essential for self-dimerization of HN. These findings indicate that HN has activity similar to a signal peptide, for which the Leu9-Leu11 region, particularly Leu10, functions as a core domains,and suggest that self-dimerization of HN is a process essential for its neuroprotective function.
3) Mechanism of HN activation
We found that HN with a D-Ser substitution at position 14 exerted a grater neuroprotective activity than HN by two to three orders of magnitude, whereas D-Ser substitution at position 7 did not affect the HN action. The results demonstrated that the neuroprotective function of HN is regulated by D-racemation of Ser14.
This study provides definite clues to the understanding of how HN protects neuronal cells from AD relevant insults Alzheimer's Disease (AD) Less

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (27 results)

All Other

All Publications (27 results)

  • [Publications] Hashimoto Y, Kita Y, et al.: "Humanin antagonists : mutants that interfere with dimerization inhibit neuroprotection by Humanin"Eur.J.Neurosci.. (in press). (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Terashita K, Kita Y, et al.: "Two serine residues distinctly regulate the rescue function of Humanin, an inhibiting factor of Alzheimer's disease-related neurotoxicity : functional potentiation by isomerization and dimerization"J.Neurochem. 85. 1521-1538 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tajima H, Kita Y, et al.: "Evidence for in vivo production of Humanin peptide, a neuroprotective factor against Alzheimer's disease related insults"Neurosci.Lett.. 324. 227-231 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hashimoto Y, Kita Y, et al.: "Neurotoxic mechanisms by Alzheimer's disease-linked N141I mutant presenilin2"J.Pharmacol.Exp.Ther.. 300. 736-745 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hashimoto Y, Kita Y, et al.: "Neurotoxic mechanisms by Alzheimer's disease-linked M146L presenilin1 : involvement of NO synthase via a novel pertussis toxin target"J.Neurochem.. 80. 426-437 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Matsuda S, Kita Y, et al.: "c-Jun N-terminal kinase (JNK)-interacting protein-1b/islet-brain-1 scaffolds Alzheimer's amyloid precursor protein with JNK"J.Neurosci.. 21. 6597-6607 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hashimoto Y, Kita Y, et al.: "Detailed characterization of neuroprotection by a rescue factor Humanin against various Alzheimer's disease-relevant insults"J.Neurosci.. 21. 9235-9245 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hashimoto Y, Kita Y, et al.: "A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Aβ"Proc.Natl.Acad.Sci.USA 98,6336-6341 Correction in : Proc.Natl.Acad.Sci.USA 2001 98,12854.. 98. 6336-6341 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hashimoto, Terashita K, Niikura T, Yamagishi Y, Ishizaka M, Kanekura K, Chiba T, Yamada M, Kita Y, Aiso S, Matsuoka M, Nishimoto I: "Humanin antagonists : mutants that interfere with dimerization inhibit neuroprotection by Humanin"Eur.J.Neurosci.. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Terashita K^*, Hashimoto Y^*, Niikura T, Tajima H, Yamagishi Y, Ishizaka M, Kawasumi M, Chiba T, Kanekura K, Yamada M, Nawa M, Kita Y, Aiso S, Nishimoto I: "Two serine residues distinctly regulate the rescue function of Humanin, an inhibiting factor of Alzheimer's disease-related neurotoxicity : functional potentiation by isomerization and dimerization"J.Neurochem. 85. 1521-1538 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tajima H, Niikura T, Hashimoto Y, Ito Y, Kita Y, Terashita K, Yamazaki K, Koto A, Aiso S, Nishimoto I: "Evidence for in vivo production of Humanin peptide, a neuroprotective factor against Alzheimer's disease related insults"Neurosci.Lett.. 324. 227-231 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hashimoto Y, Niikura T, Ito Y, Kita Y, Terashita K, Nishimoto I: "Neurotoxic mechanisms by Alzheimer's disease-linked N1411 mutant presenilin2"J.Pharmacol.ExTher.. 300. 736-745 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hashimoto Y, Ito Y, Arakawa E, Kita Y, Terashita K, Niikura T, Nishimoto I: "Neurotoxic mechanisms triggered by Alzheimer's disease-linked mutant M146L presenilin 1 : involvement of NO synthase via a novel pertussis toxin target."J.Neurochem.. 80. 426-437 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Matsuda S, Yasukawa T, Homma Y, Shao Z, Ito Y, Niikura T, Hiraki T, Hirai S, Ohno S, Kita Y, Kawasumi M, Kouyama K, Yamamoto T, Kyriakis JM, Nishimoto I: "c-Jun N-terminal kinase (JNK)-interacting protein-1b/islet-brain-1 scaffolds Alzheimer's amyloid precursor protein with JNK"J.Neurosci.. 21. 6597-6607 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hashimoto Y, Niikura T, Ito Y, Sudo H, Hata M, Arakawa E, Abe Y, Kita Y, Nishimoto I: "Detailed characterization of neuroprotection by a rescue factor Humanin against various Alzheimer's disease-relevant insults"J.Neurosci.. 21. 9235-9245 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hashimoto Y, Niikura T, Tajima H, Yasukawa T, Sudo H, Ito Y, Kita Y, Kawasumi M, Kouyama K, Doyu M, Sobue G, Koide T, Tsuji S, Lang J, Kurokawa K, Nishimoto I: "A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Ab."Proc.Natl.Acad.Sci.USA (Correction in: Proc.Natl.Acad.Sci.USA. 2001; 98: 12854). 98. 6336-6341 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tajima H.et al.: "Evidence for in vivo production of Humanin peptide, a neuroprotective factor against Alzheimer's disease related insults"Neuroscience Letters. 324. 227-231 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hashimoto Y et al.: "Neurotoxic mechanisms triggered by Alzheimer's disease-linked mutant M146L presenilin 1 : involvement of NO synthase via a novel pertussis toxin target"Journal of Neurochemistry. 80. 426-437 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hashimoto Y et al.: "Detailed characterization of neuroprotection by a rescue factor Humanin against various Alzheimer's disease-relevant insults"Journal of Neuroscience. 21・23. 9235-9245 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Matsuda S et al.: "c-Jun N-terminal kinase (JNK)-interacting protein-1b/islet-brain-l scaffolds Alzheimer's amyloid precursor protein with JNK"Journal of Neuroscience. 21・17. 6597-6607 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hashimoto Y et al.: "A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Aβ"Proceedings of the National Academy of Sciences of the United States of America. 98・11. 6336-6341 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tajima H., et al.: "Evidence for in vivo production of Humanin peptide, a neuroprotective factor against Alzheimer's disease related insults"Neuroscience Letters. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hashimoto Y, et al: "Neurotoxic mechanisms triggered by Alzheimer's disease-linked mutant M146L presenilin 1 : involvement of NO synthase via a novel pertussis toxin target"Journal of Neurochemistry. 80. 426-437 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hashimoto Y, et al: "Detailed characterization of neuroprotection by a rescue factor Humanin against various Alzheimer's disease-relevant insults"Journal of Neuroscience. 21. 9235-9245 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Matsuda S, et al: "c-Jun N-terminal kinase(JNK)-interacting protein-1b/islet-brain-1 scaffolds Alzheimer's amyloid precursor protein with JNK"Journal of Neuroscience. 21. 6597-6607 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Niikura T, et al: "Insulin-like growth factor I(IGF-I) protects cells from apoptosis by Alzheimer's V642I mutant amyloid precursor protein through IGF-I receptor in an IGF-binding protein-sensitive manner"Journal of Neuroscience. 21. 1902-1910 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hashimoto Y, et al: "A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Aβ"Proceedings of National Academy of Science USA. 98. 6336-6341 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2002-04-01   Modified: 2022-01-20  

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