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2002 Fiscal Year Final Research Report Summary

Detailed characterization of Humanin, a newly identified anti-Alzheimer's disease peptide and potential starting point for development of the first curative therapy for Alzheimer's disease

Research Project

Project/Area Number 13307022
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Neurology
Research InstitutionKEIO UNIVERSITY

Principal Investigator

NISHIMOTO Ikuo  Keio University, School of Medicine, Professor, 医学部, 教授 (80180652)

Co-Investigator(Kenkyū-buntansha) NIIKURA Takako  Keio University, School of Medicine, Instructor, 医学部, 助手 (10301491)
HASHIMOTO Yuichi  Keio University, School of Medicine, Instructor, 医学部, 助手 (00317330)
MATSUOKA Masaaki  Keio University, School of Medicine, Associate Professor, 医学部, 助教授 (70222297)
Project Period (FY) 2001 – 2002
KeywordsHumanin / Alzheimer's disease / neurodegenerative disease / dimerization / serine isomerase / receptor / 生体内発現
Research Abstract

No fundamental therapy for Alzheimer's disease (AD) has so far been developed. Humanin is a newly identified peptide that suppresses cell death by Alzheimer's disease (AD)-related insults. We have investigated the structure/function relationship for the neuroprotective function of HN peptide. When either Pro3, Ser7, Cys8, Leu9, Leu 12, Thr13, Ser14, or Pro19 is changed to Ala in full-length HN, the HN derivatives lose its neuroprotective activity. Pro3-Pro19 turned out to be the core domain for neuroprotection by HN. HN forms a homodimer, which is essential for HN neuroprotection, and that Ala substitution for Ser7 or Leu9 nullifies homodimerization by HN. HN should be secreted and be able to act from the outside, indicating that a certain cell-surface receptor is the target of HN. HN immunoreactivity is detected in some of the intact large neurons in the occipital lobe of an AD brain, but not in other brain regions or in an age-matched control brain. In mice, 3 kDa immunoreactive pept … More ide, the deduced molecular weight of HN, has been detected in the testes and colons of 3-week-old mice. This immunoreactivity disappears in the colon of 12-week-old mice, pointing to the age-dependent regulation of HN production. We identified TRIM11 as a HN-interacting protein, a member of a protein family containing a tripartite motif (TRIM). TRIM11 is composed of a RING finger domain, which is a putative E3 ubiquitin ligase. Notably, TRIM11 ubiquitinizes and degrades HN intracellularly. We also found that the potentiation of HN neuroprotective function by Gly substitution for Ser14 is specifically mimicked by D-Ser isomerization. Therefore, it is conceivable that HN peptide is transcribed and translated from the HN gene and then converted to the maximally active form by posttranslational modification at Ser14, that is, D-Ser14 isomerization. Considering that insulin-like growth factor-binding protein 3 is an HN-binding protein in the blood [20], it is an attractive hypothesis that HN is mainly produced in tissues outside the central nervous system (CNS), transferred by binding to the binding protein, and further activated as it passes through the blood-brain barrier, and is delivered to CNS neurons. Considering the broad specificity of its rescue activity to AD-relevant insults, HN is a promising seed for AD therapy aiming the complete suppression of neuronal loss. Less

  • Research Products

    (13 results)

All 2003 2002 2001 2000

All Journal Article (12 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Identification of essential amino acids in Humanin, a neuroprotective factor against Alzheimer's disease relevant insults.2003

    • Author(s)
      Yamagishi Y., et al.
    • Journal Title

      Peptides 24

      Pages: 585-595

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Two serine residues distinctly regulate the rescue function of Humanin, an inhibiting factor of Alzheimer's disease-related...2003

    • Author(s)
      Terashita K., et al.
    • Journal Title

      The Journal of Neurochemistry 85

      Pages: 1521-1538

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] A tripartite motif protein TRIM11 binds and destabilizes Humanin, a neuroprotective peptide against Alzheimer's disease-relevant insults.2003

    • Author(s)
      Niikura T., et al.
    • Journal Title

      The European Journal of Neuroscience 17

      Pages: 1150-1158

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Identification of essential amino acids in Humanin, a neuroprotective factor against Alzheimer's disease relevant insults.2003

    • Author(s)
      Yamagishi Y., et al.
    • Journal Title

      Peptides 24(4)

      Pages: 585-595

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Two serine residues distinctly regulate the rescue function of Humanin, an inhibiting factor of Alzheimer's disease-related neurotoxicity.2003

    • Author(s)
      Terashita K., et al.
    • Journal Title

      The Journal of Neurochemistry 85(6)

      Pages: 1521-1538

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] A tripartite motif protein TRIM11 binds and destabilizes Humanin, a neuroprotective peptide against Alzheimer's disease-relevant insults.2003

    • Author(s)
      Niikura T., et al.
    • Journal Title

      The European Journal of Neuroscience 17(6)

      Pages: 1150-1158

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Evidence for in vivo production of Humanin peptide, a neuroprotective factor against Alzheimer's disease-related insults.2002

    • Author(s)
      Tajima H., et al.
    • Journal Title

      Neuroscience Letters 324

      Pages: 227-231

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Evidence for in vivo production of Humanin peptide, a neuroprotective factor against Alzheimer's disease-related insults.2002

    • Author(s)
      Tajima H., et al.
    • Journal Title

      Neuroscience Letters 324(3)

      Pages: 227-231

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Detailed characterization of neuroprotection by a rescue factor Humanin against various Alzheimer's disease-relevant insults.2001

    • Author(s)
      Hashimoto Y, et al.
    • Journal Title

      The Journal of Neuroscience 21

      Pages: 9235-9245

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Aβ.2001

    • Author(s)
      Hashimoto Y, et al.
    • Journal Title

      Proceedings of National Academy of Sciences, USA 98

      Pages: 6336-6341

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Detailed characterization of neuroprotection by a rescue factor Humanin against various Alzheimer's disease-relevant insults.2001

    • Author(s)
      Hashimoto Y., et al.
    • Journal Title

      The Journal of Neuroscience 21(23)

      Pages: 9235-9245

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Aβ.2001

    • Author(s)
      Hashimoto Y., et al.
    • Journal Title

      Proceedings of National Academy of the United States of America 98(22)

      Pages: 6336-6341

    • Description
      「研究成果報告書概要(欧文)」より
  • [Patent(Industrial Property Rights)] 神経細胞死を抑制するポリペプチド、Humanin2000

    • Inventor(s)
      西本征央
    • Industrial Property Rights Holder
      学校法人慶應義塾
    • Industrial Property Number
      PCT/JP00/06314
    • Filing Date
      2000-09-14
    • Description
      「研究成果報告書概要(和文)」より

URL: 

Published: 2006-07-11  

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