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Amyloid beta protein deposition : cause or consequence of neuronal loss?

Research Project

Project/Area Number 09835004
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

YAMAZAKI Tsuneo  The Universi of Tokyo, Granduate School of Medicine, Instructor, 大学院・医学系研究科, 助手 (80200658)

Co-Investigator(Kenkyū-buntansha) IHARA Yasuo  The Universi of Tokyo, Granduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (60114386)
Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1998: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1997: ¥1,700,000 (Direct Cost: ¥1,700,000)
KeywordsAlzheimer's disease / Amyloid beta protein / Neuronal cell death / コレステロール
Research Abstract

Amyloid beta protein (Abeta) deposition is one of the major pathological hallmarks in Alzheimer's disease (AD) brains.. Abeta is classified into two major subspecies, Abeta40 and Abeta42, and Abeta42 is found to be the initial depositing subspecies which facilitates Abeta deposition in a nucleation depending manner. In vitro Abeta is neuro toxic for cultural neurons, thus it is widely believed that aggregated Abeta causes neuronal dysfunction and loss in AD brains (Abeta cascade theory). Accordingly, discovering reagents which reduce the production of Abeta, especially Abeta42 might be one of the therapeutic objects. However, the intracellular Abeta production compartments which could be the drug target have not been determined.. Thus, our first experimental aim was to clarify the organelles producing Abeta. Using cultural cells and a sensitive Abeta ELISA system, we found that : 1) Abeta4O and Abeta42 are produced in the Golgi apparatus ; 2) some Abeta42 is also created in endoplasmic … More reticulum.
According to the Abeta cascade theory, in vivo neurons should be sensitive to aggregated Abeta. However, no such evidence has been presented so far. Furthermore, recent reports using amyloid precursor protein transgenic mice showed that neuronal loss was not observed even in the presence of numerous Abeta deposition in brains. These results may point out that Abeta deposition is not the cause of cell death but the consequence. To check this possibility, we focused on the effects of cholesterol and sphingolipid metabolism on Abeta production, because the geno- types of cholesterol carrier protein apoE is a major risk factor for AD.We looked at the Abeta production employing a series of drugs which affect the cholesterol and sphigolipid metabolism using K293 cells , but could not get significant effects.. Recently, we found that Abeta and cholesterol share the same special compartment in a neuroblastoma cell line. This finding may suggest that neuronal membrane lipid metabolism effects on Abeta production specifically. Regarding on this notion, now we are continuing some experiments using human materials. Less

Report

(3 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • Research Products

    (21 results)

All Other

All Publications (21 results)

  • [Publications] T.Yamazaki: "Molecular pathology of Alzheimer's disease" Neuropathology. 17. 263-269 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] J.Nakabayashi: "Amyloid β-protein (Aβ) accumulation in the putamen and mammillary body during aging and in Alzheimer disease" J.of Neuropathology and Experimental Neurology. 57. 343-352 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] T.Yamazaki: "Effects of specific protease inhibitors on amyloid β-protein 42 secretion" Neurobiology of Aging. 19. S77-S79 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] H.Funato: "Astrocytes containing amyloid β-protein (Aβ)-positive granules are associated with A beta 40-positive diffuse plaques in the aged human brain" American Journal of Pathology. 152. 983-992 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 山崎恒夫: "アルツハイマー病" 蛋白質核酸酵素. 42. 2393-2398 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 山崎恒夫: "Alzheimer神経原線維変化-最近の知見" Clinical Neuroscience. 16. 240-241 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] T.Yamazaki: "Molecular pathology of Alzheimer's disease" Neuropathology. 17. 263-269 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] J.Nakabayashi: "Amyloid beta-protein (Abeta) accumulation in the putamen and mammillary body during aging and in Alzheimer disease" J Neuropathol Exp Neurol. 57. 343-352 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] T.Yamazaki: "Effects of specific protease inhibitors on amyloid beta-protein 42 secretion" Neurobiol Aging. 19. S77-S79 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] F.Funato: "Astrocytes containing amyloid beta-protein (Abeta) -positive granules are associated with Abeta40-positive diffuse plaques in the aged human brain." Am J Pathol. 152. 983-992 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] T.Yamazaki: "Alzhemer's disease" Tanpakushitsu Kakusan Koso. 42. 2393-2398 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] T.Yamazaki: "Alzhemer's neurofibrilary tangle-new knowledge" Clinical Neuroscience. 16. 240-241 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] T.Yamazaki: "Molecular pathology of Alzheimer's disease" Neuropathology. 17. 263-269 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] J.Nakabayashi: "Amyloid β-protein(Aβ)accumulation in the putamen and mammillary body during aging and in Alzheimer disease" J.of Neuropathology and Experimental Neurology. 57. 343-352 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] T.Yamazaki: "Effects of specific protease inhibitors on amyloid β-protein 42 secretion" Neurobiology of Aging. 19. S77-S79 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] H.Funato: American Journal of Pathology. 152. 983-992 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 山崎恒夫: "アルツハイマー病" 蛋白質 核酸 酵素. 42. 2393-2398 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] 山崎恒夫: "Alzheimer神経原線維変化-最近の知見" Clinical Neuroscience. 16. 240-241 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 山崎恒夫: "AGEとアルツハイマー病" 治療学. 32. 62-64 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Bode,C.W: "Intracellular generation and accumulation of amyloid β-peptide terminating at amino acid42" Journal of Biological Chemistry. 272. 16085-16088 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Yamazaki,T.: "Specific increase in amyloid β-protein 42 secretion ratio by calpain inhibition" Biochemistry. 36. 8377-8383 (1997)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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