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1988 Fiscal Year Final Research Report Summary

Identification of the components of paired helical filaments

Research Project

Project/Area Number 62480210
Research Category

Grant-in-Aid for General Scientific Research (B)

Allocation TypeSingle-year Grants
Research Field Neurology
Research InstitutionTokyo Metropolitan Institute of Gerontology

Principal Investigator

IHARA Yasuo  Tokyo Metropolitan Institute of Gerontology, 臨床系2生理, 室長 (60114386)

Co-Investigator(Kenkyū-buntansha) 関 俊子  東京都老人総合研究所, 臨床系2生理, 研究助手
三浦 玲子  東京都老人総合研究所, 臨床系2生理, 研究助手
OGAWARA Midori  see above, 臨床系2生理, 研究助手 (60100111)
TAMAOKA Akira  see above, 臨床系2生理, 研究員 (50192183)
MORI Hiroshi  see above, 臨床系2生理, 研究員 (10159189)
MIURA Reiko  see above
SEKI Toshiko  see above
Project Period (FY) 1987 – 1988
KeywordsAlzheimer's disease / ubiquitin / tau / protein sequencing / protein sequeneing
Research Abstract

One of the hallmarks of Alzheimer's disease (AD) is the progressive accumulation of unusual neuronal fibers, termed paired helical filaments (PHF). Since the concentration of PHF in cerebral cortex was suggested to well correlated with the degree of dementia, much effort has been concentrated to the elucidation of the nature of PHF. However, the component analysis of PHF has been only slowly progressing because of remarkable insolubility of PHF.
Immunocytochemical studies using antibodies to cytoskeletal proteins provided conflicting data on the components of PHF due solely to immunological cross-reactivities. To avoid such ambiguity, we developed a protein chemical approach to the identification of the PHF components. After treatment with formic acid, PHF were digested with lysylendopeptidase and the produced peptides were separated by PHLC. All major peaks were analyzed for their amino acid compositions and sequences. From the PHF digests, proteolytic fragments of Ubiquitin, tau and p … More rotein were sequenced. ubiquitin appears to be of a conjugated form in PHF, while its target protein remains unidentified. Tau is integrated into PHF at its carboxyl third. the presence of protein fragments is best interpreted as being due to contamination of amyloid filaments in the PHF preparation. Thus, ubiquitin and tau are the two definite components of PHF.
We also re-examined AD brain sections using antibodies to human tau, one of the definite components of PHF. The tau immunostaining revealed extensive meshworks throughout AD cortex in addition to senile plaques and neurofibrillary tangles. The meshwork was most dense in layers 3 and 5 of the association cortex, suggesting a close relationship with pyramidal cells. Further observations showed that the meshwork consists of innumerable abnormaly curly fibers which were 5-30 um long and often swollen at the one end. The curly fibers appears to come from pyramidal cell bodies and their dendrites. These morphological features strongly suggest that these curly fibers represent somatodendritic sprouting. This hypothesis could explain why several fetal antigens are expressed in the AD brain. This is also compatible with a recent unexpected finding that nerve growth activities are increased in AD brain compared with normal controls. Less

  • Research Products

    (11 results)

All Other

All Publications (11 results)

  • [Publications] Mori H,Kondo J.Ihara Y: Science. 235. 1641-1644 (1987)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kuzuhara S,Mori H,Izumiyama N,Yoshimura M,Ihara Y: Acta Neuropath. 75. 345-353 (1988)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Uchida Y,Ihara Y,Tomonaga M: Biochem Biophys Res Comm. 150. 1263-1267 (1988)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ishiguro K,Ihara Y,Uchida T,Imahori K: J Biochem. 104. 319-321 (1988)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ihara Y: Brain Res. 459. 138-144 (1988)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kondo J,Honda T,Mori H,Hamada Y,Miura R,Ogawara M,Ihara Y: Neuron. 1. 827-834 (1988)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Mori H; Kondo J; Ihara Y: "Ubiquitin is a component of paired helical filaments in Alzheimer's disease." Science. 235. 1641-1644 (1987)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kuzuhara S; Mori H; Izumiyama N; Yoshimura M; Ihara Y: "Lewy bodies are ubiquitinated. A light and electron microscopic immunocytochemical study." Acta Neuropath. 75. 345-353 (1988)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ishiguro K; Ihara Y; Uchida T; Imahori K: "A novel tubulin-dependent protein kinase forming a paired helical filament epitope on tau." J Biochem (Tokyo). 104. 319-321 (1988)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ihara Y: "Massive somatodendritic sprouting of cortical neurons in Alzheimer's disease." Brain Res. 459. 138-144 (1988)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kondo J; Honda T; Mori H; Hamada Y; Miura R; Ogawara M; Ihara Y: "The carboxyl third of tau is tightly bound to paired helical filaments." Neuron. 1. 827-834 (1988)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 1990-03-20   Modified: 2017-04-05  

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