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1998 Fiscal Year Final Research Report Summary

Studies on the tau lysosomal proteolytic pathway

Research Project

Project/Area Number 09835002
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field 老化(加齢)
Research InstitutionThe University of Tokyo

Principal Investigator

OYAMA Fumitaka  The Universi of Tokyo, Graduate School of Medicine, Lecturer, 大学院・医学系研究科, 講師 (40194641)

Co-Investigator(Kenkyū-buntansha) IHARA Yasuo  The Universi of Tokyo, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (60114386)
Project Period (FY) 1997 – 1998
KeywordsAlzheimer's disease / tau / lysosome / chloroquine myopathy
Research Abstract

Tau is the major component of paired helical filaments (PHF) in Alzheimer's disease (AD) brain. The presence of tau-immunoreactive, PHF-like fibrils was reported in the muscle affected by inclusion body myositis (IBM), and amorphous tau deposits were recently found in chloroquine myopathy (CM), an experimental model for IBM.We investigated CM to obtain insight into PHF formation in AD brain. In CM tau mRNA level was transiently upregulated in the early phase, while tau itself slowly accumulated in the late phase. The temporal profiles of tau mRNA levels and its accumulation were very similar to those of beta-amyloid protein precursor (APP) and its carboxyl-terminal fragments, both of which have been known to be degraded in lysosomes. Immunocytochemistry showed that tau progressively accumulated in the rimmed vacuoles with increased acid phosphatase activities, and immunoelectron microscopy demonstrated that tau was located within the vacuoles. These results suggest that tau is degraded … More in lysosomes or their functional equivalents in the muscle.
To confirm the tau degradation pathway in lysosome we analyzed the autophagolysosomes from liver of the transgenic rat overexpressing the shortest form of human tau under transcriptional control of the chicken beta-actin promoter. We found that tau was present in autophagolysosomes from leupeptin-treated liver, whereas it was not detected in those from leupeptin-untreated liver. These results suggest that tau is also degraded in lysosomes in liver. The observations in both muscle and liver prompted us to search for a receptor for tau in rat brain lysosomes. Rat brain lysosomal membranes were separated by SDS polyacrylamide gel electrophoresis, transferred to nitrocellulose membrane, and incubated with tau. We found that the proteins with the molecular weight of 130, 100, and 76 kDa specifically bound tau. On the other hand, we identified MP5O (glutamate dehydrogenase) in the lysosomal fraction as a possible tau-binding protein by use of tau affinity chromatography. Less

  • Research Products

    (11 results)

All Other

All Publications (11 results)

  • [Publications] Namekata,K.et al.: "Human transferrin (Tf) : a shingle mutation at codon 570 determined TfC1 of TfC2 variant." Human Genet.100. 457-458 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Namekata,K.et al.: "Association of transferrin C2 allele with late-onset Alzheimer's disease." Human Genet.101. 126-129 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Murakami,N.,et al.: "Accumulation of tau in autophagic vacuoles in chloroquine myopathy." J.Neuropathol.Exp.Neurol.57. 664-673 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Oyama,F.et al.: "Chloroquine myopathy suggests that tau is degraded in lysosomes : Implication for the formation of paired helical filaments in Alzheimer's disease." Neurosci.Res.31. 1-8 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Oyama,F.,et al.: "Mutant presenilin 2 transgenic mouse : effect on an age-dependent increase of amyloid β-protein (Aβ) in the brain." J.Neurochem.71. 313-322 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Namekata, K., Oyama, F., Imagawa, M., and Ihara, Y.: "Human transferrin (Tf) : a single mutation at codon 570 determined Tf C1 or Tf C2 variant." Human Genet.100. 457-458 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Namekata, K., Imagawa, M., Terashi A., Ohta, S., Oyama, F., and Ihara, Y.: "Association of transferrin C2 allele with late-onset Alzheimer's disease." Human Genet.101. 126-129 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Murakami, N., Oyama, F., Gu, Y., McLennan, IS., Nonaka, I., and Ihara, Y.: "Accumulation of tau in autophagic vacuoles in chloroquine myopathy." J.Neuropathol.Exp.Neurol.57. 664-673 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Oyama, F., Murakami, N., and Ihara, Y.: "Chloroquine myopathy suggests that tau is degraded in lysosomes : Implication for the formation of paired helical filaments in Alzheimer's disease." Neurosci.Res.1998 31. 1-8 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Oyama, F., Sawamura, N., Kobayashi K., Morishima-kawashima, M., Kuramochi, K., Ito, M., Tomita, T., Maruyama, K., Saido, TC., Iwatsubo, T., Capell, A., Walter, J., Gruberg, J., Ueyama, Y., Haase, C., and Ihara, Y.: "Mutant presenilin 2 Transgenic mouse : effect on an age-dependent increase of amyloid beta-protein (Abeta) in the brain." J.Neurochem.71. 313-322 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Oyama, F., Gu, Y., Murakami, N., Nonaka, I., and Ihara, Y.: Alzheimer's Disease : Biology, Diagnosis and Therapeutics (ed.by Iqbal et al.) Nonneural tau : Transient upregulation and subsequent accumulation of big and small tau in chloroquine myopathy.437-445 (1997)

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      「研究成果報告書概要(欧文)」より

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Published: 1999-12-08  

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