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Biochemical and molecular biological mechanisms underlying a to b cleavage and Ab biogenesis in Alzheimer disease

Research Project

Project/Area Number 12470197
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Psychiatric science
Research InstitutionSaitama Medical School

Principal Investigator

FUKATSU Ryo  Saitam Medical School, Neuropsychiatry, Professor, 医学部, 教授 (10113614)

Co-Investigator(Kenkyū-buntansha) KIMURA Koichi  Hokkaido Institute of Technology, Bioscience, Associate Professor, 工学部, 助教授 (90177915)
TSUZUKI Kayo  Sapporo Medical University, Microbiology, Instructor, 医学部, 助手 (60207420)
Project Period (FY) 2000 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥13,000,000 (Direct Cost: ¥13,000,000)
Fiscal Year 2002: ¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2001: ¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2000: ¥6,600,000 (Direct Cost: ¥6,600,000)
KeywordsAlzheimer's disease / Amyloid β peptide / β-secretase / Amyloid precursor protein / chloroquine / myocyte-culture / Anti-sense oligonucleotide / Aβ / β切断酵素抗体 / β切断酵素発現 / 免疫病理学 / 分子生物学 / Aβブレイカー蛋白 / Aβブレイカー蛋白遺伝子 / 遺伝子導入 / マウス腹腔マクロファージ
Research Abstract

Alzheimer's disease (AD) is the most common but complex and heterogenous genetic disorders of dementia. Neuropathology of brains affected with complex and heterogenous disorders of AD shows rather a homogenous feature. This inevitable fact simply indicates that accumulation and aggregation of Amyloid β(Aβ) is the primary cause of AD. Aβ is an about 40 amino acid residue peptide, derived, by two sequential cleavages, from APP. The proteases involved are β-secretase, as the novel aspartyl protease, beta-site APP cleaving enzyme (BACE), and γ-secretase, a multimeric complex containing the presenilins. It is quite reasonable that the balance between the generation and the degradation/clearance of Aβ might be altered in the brains affected with AD. Aβis a about 40 amino acid residue peptide, derived, by two sequential cleavages, from amyloid precursor protein (APP). The proteases involved are β-secretase, as the novel aspartyl protease, (BACE), and γ-secretase, a multimeric complex containing the presenillins.
On the other hand, recently we have established an excellent experimental culture myocyte system under the presence or the absence of chloroquine (CQN) to study APP processing to generate Aβ. In this experiment, we have examined the balance between the generation and the degradation/clearance of Aβ. It is shown that BACE mRNA expression is up-regulated, and Aβ amount is increased under CQN treatment, and that antisense oligonucleotides for BACE treatments reduce the level of C99, β-secretase cleaved C-terminus APP fragment and Aβ level. The inhibition of β-secretase activity might have great therapeutic potential in AD treatment.

Report

(4 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (38 results)

All Other

All Publications (38 results)

  • [Publications] Yoshida T, Fukatsu R et al.: "Cultured myocyte systems under chloroquine as an experimental model to study APP processing for Aβ production"Brain Research. (in press). (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Totsuka T, Fukatsu R et al.: "Inhibition of β secretase expression decreases Aβ production in an experimental cultured myocte systems"Brain Research. (in press). (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kimura K, Fukatsu R, et al.: "Expression of Aβ braker peptide inhibits Aβ production in cultured myocyte systems"Neuroscience Letter. (in press). (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fukatsu R, Tuzuki K et al.: "Alzheimer's senile pathology observed in Membranous Lipodystrophy (Nasu-Hakola disease)"Brain Pathology. 10・4. 516 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tuzuki K, Fukatsu R et al.: "Transthyretin binds amyloid β peptides, Aβ1-42 and Aβ1-40 to form complex in autopsied human kidney -possible role of transthyretin for Aβ sequestration-"Neuroscience Letters. 281. 171-174 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 深津 亮: "歯状核赤核・淡蒼球ルイ体萎縮症(DRPLA)"老年精神医学雑誌. 14(3). (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 深津 亮, 続 佳代: "IV病因・病態「臨床精神医学講座」special issue第9巻 アルツハイマー病"松下正明総編集 三好好峰、小坂憲司 責任編集 中山書店 東京. 12 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Totsuka T, Fukatsu R, et al.: "Cultured myocyte systems under chloroquine as an experimental model to study APP processing for Aβ production"Brain Research (in press). (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Totsuka T, Fukatsu R, et al.: "Inhibition of β secretase expression Aβ production in an experimental cultured myocyte systems"Brain Research (in press). (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kimura K, Fukatsu R, et al.: "Expression of Aβ braker peptide inhibits Aβ production in cultured myocyte systems"Neuroscinece Letter (in press). (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fukatsu R, Tuzuki K, et al.: "Alzheimer's senile pathology observed in Membranous Lipodystrophy (Nasu-Hakola disease)"Brain Pathology. 10-4. 516-516 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tuzuki K, Fukatsu R, et al.: "Transthyretin binds amyloid β peptides, Aβ1-42 and Aβ1-40 to form complex in autopsied human kidney - possible role of transthyretin for Aβ sequestration"Neuroscience Letters. 281. 171-174 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fukatsu R, Fujii M, Murakami S: "Neuropsychological disturbances and pathological processes underlying Alzheimer's disease - with special reference to visuospatial disorganization and neuropathology -"Seisinnsinnkeisi. 104. 139-143 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fukatsu R: "Dentatorubural pallidoluysian atrophy (DRPLA)"Rounennseisinnigakuzassi. 14. 330-336 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fukatsu R, Tuzuki K: "Amyloid precursor protein and Amyloid β protein, KEY WORD Seisinn, 2nd edition"Senntannigakusya, Tokyo. 144-147 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fulatsu R: "Alzheimer's disease, Konniti no Tiryousisinn"Igakusyoinn, Tokyo. 638-639 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Totsuka T, Fukatsu R et al.: "Cultured myocyte systems under chloroquine as an experimental model to study APP processing for Aβ production"Brain Research. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Totsuka T, Fukatsu R et al.: "Inhibition of β secretase expression decreases Aβ production in an experimental cultured myocte systems"Brain Research. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kimura K, Fukatsu R, et al.: "Expression of Aβ braker peptide inhibits Aβ production in cultured myocyte systems"Neuroscience Letter. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Fukatsu R, Tuzuki K et al.: "Alzheimer's senile pathology observed in Membranous Lipodystrophy (Nasu-Hakola disease)"Brain Pathology. 10・4. 516 (2000)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tuzuki K, Fukatsu R et al.: "Transthyretin binds amyloid β peptides, Aβ 1-42 and Aβ 1-40 to form complex in autopsied human kidney-possible role of transthyretin for Aβ sequestration-"Neuroscience Letters. 281. 171-174 (2000)

    • Related Report
      2002 Annual Research Report
  • [Publications] 深津 亮: "歯状核赤核・淡蒼球ルイ体萎縮症(DRPLA)"老年精神医学雑誌. 14(3). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] 深津 亮, 続 佳代: "IV病因・病態「臨床精神医学講座」special issue第9巻 アルツハイマー病"松下正明総編集 三好好峰、小坂憲司 責任編集 中山書店 東京. 12 (2000)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tsuzuki K, Fukatsu R, et al.: "Transthyretin binds amyloid β peptides, Aβ1-42 and Aβ1-4O to form complex in the autopsied human kidney -possible role of transthyretin for Aβ sequestration-"Neuosience Letters. 281. 171-174 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] 深津 亮, 続 佳代, 他: "Nasu-Hakola病に認められるアルツハイマー病変に関する検討-アミロイド変化の生化学的、免疫病理学的検討-"Neuropathology. 20. 154 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tsuzuki K, Fukatsu R, et al.: "Prion protein is colocalized in amyloid βprotein aggregates in the rimmed vacuoles of chloroquine myopathy in rat"Neuroscience Letters. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Fukatsu R, Tsuzuki K, et al.: "Alzheimer's senile pathology observed in Membranous Lipodystrophy (Nasu-Hakola disease)"Brain Pathology. 10・4. 516 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Fukatsu R, Tsuzuki K, et al.: "Cultured myocyte systems under chloroquine as an experimental model to study APP, PS-1 processing for Aβ production"Brain Research. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Nakano N, Hatakeyama Y, et al.: "Eye-Head Coordination Abnormalities and Regional Cerebral Blood Flow in Alzheimer's Disease"Prob Neuro-Psychopharmacol & Biol Psychiat. 23. 1053-1062 (1999)

    • Related Report
      2001 Annual Research Report
  • [Publications] 深津 亮, 続 佳代: "IV 病因・形態 「臨床精神医学講座」special issue 第9巻 アルツハイマー病"松下正明 総集編 三好好峰, 小坂憲司 責任編集 中山書店 東京. 12 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tsuzuki K,Fukatsu R, et al.: "Transthyretin binds amyloid β peptides, Aβ1-42 and Aβ1-40 to form complex in the autopsied human kidney -possible role of transthyretin for Aβ sequestration-"Neuosience Letters. 281. 171-174 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 深津亮,続佳代 他: "Nasu-Hakola病に認められるアルツハイマー病変に関する検討-アミロイド変化の生化学的、免疫病理学的検討-"Neuropathology. 20. 154 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tsuzuki K,Fukatsu R, et al.: "Prion protein is colocalized in amyloid β protein aggregates in the rimmed vacuoles of chloroquine myopathy in rat"Neuroscience Letters. (in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Fukatsu R,Tsuzuki K, et al.: "Alzheimer's senile pathology observed in Membranous Lipodystrophy (Nasu-Hakola disease)"Brain Pathology. 10・4. 516 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Fukatsu R,Tsuzuki K, et al.: "Cultured myocyte systems under chloroquine as an experimental model to study APP, PS-1 processing for Aβ production"Brain Research. (in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nakano N,Hatakeyama Y, et al: "Eye-Head Coordination Abnormalities and Regional Cerebral Blood Flow in Alzheimer's Disease"Prob Neuro-Psychopharmacol & Biol Psychiat. 23. 1053-1062 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] 深津亮,続佳代: "IV 病因・病態「臨床精神医学講座」special issue 第9巻 アルツハイマー病"松下正明 総集編 三好好峰,小坂憲司 責任編集 中山書店 東京. 12 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 藤井充,村上新治,深津亮: "IV 病因・病態「臨床精神医学講座」special issue 第9巻 アルツハイマー病"松下正明 総集編 三好好峰,小坂憲司 責任編集 中山書店 東京. 23 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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