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Neuroprotective mechanism of apolipoprotein E

Research Project

Project/Area Number 14599008
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field 細胞死(アポトーシス)
Research InstitutionEhime University

Principal Investigator

MITSUDA Noriaki  School of Medicine, Ehime University, Dept.of Physiology, Associate Professor, 医学部, 助教授 (10314329)

Co-Investigator(Kenkyū-buntansha) MAEDA Nobuji  School of Medicine, Ehime University, Dept.of Physiology, Professor, 医学部, 教授 (50036464)
Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2003: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2002: ¥2,600,000 (Direct Cost: ¥2,600,000)
KeywordsApolipoprotein E / reelin / neuroprotection / Tau / リン酸化 / GSK-3β
Research Abstract

Specific Aim : In the brain, apolipoprotein E(ApoE) is secreted from astrocytes and microglias, and plays important roles in lipid transportation. Furthermore, ApoE may protect neurons from many kinds of insults. Our aim is to elucidate the molecular mechanisms where ApoE protect neurons.
Results : When primary neurons were cultured under serum-free conditions, they underwent cell deaths. When ApoE3 was added to the serum-free medium, their deaths were significantly inhibited, On the other hand, when ApoE4 was added to the serum-free medium, their deaths were significantly promoted. Tau protein in the neurons were significantly phosphorylated, then. To substantiate this concept, we mated Reelin-deficient mice to ApoE-deficient mice and found that in the absence of Reelin, tau-phosphorylation in neurons of the brain increased as the amount of ApoE decreased. Paralleling the change in tau-phosphorylation levels, we found that GSK-3β activity increased in Reelin-deficient mice and further increased in mice lacking both Reelin and ApoE. CDK-5 activity was similar in mice lacking Reelin, ApoE, or both. GSK-3β and CDK-5 activity increased in Dab1-deficient mice, independent of ApoE levels. Further supporting the idea that increased tau-phosphorylation results primarily from increased kinase activity, the activity of 2 phosphatases were similar in all conditions tested.
Conclusions : These data support a novel, ligand-mediated signal transduction cascade-initiated by the assembly of a RAD complex that suppresses kinase activity and controls tau-phosphorylation.

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (10 results)

All Other

All Publications (10 results)

  • [Publications] Nobutaka Ohkubo et al.: "Apolipoprotein E and Reelin ligands modulate tau phosphorylation through an apolipoprotein E receptor/disabled-1/glycogen synthase kinase-3beta cascade."FASEB Journal. 17. 295-297 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Atsuyuki Morishima et al.: "NFκB regulates plasma apolipoprotein A-I and HDL-cholesterol through inhibition of PPARα"Journal of Biological Chemistry. 278. 38188-38193 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kohji Mori et al.: "L-Serine-mediated release of apolipoprotein E and lipids from microglial cells."Experimental Neurology. 185. 220-231 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nobutaka Ohkubo et al.: "Apolipoprotein E and Reelin ligands modulate tau phosphorylation through an apolipoprotein E receptor/disabled-1/glycogen synthase kinase-3beta cascade."FASEB Journal. 17. 295-297 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Atsuyuki Morishima et al.: "KFκB regulates plasma apolipoprotein A-I and HDL-cholesterol through inhibition of PPARα"Journal of Biological Chemistry. 278. 38188-38193 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kohji Mori et al.: "L-Serine-mediated release of apolipoprotein E and lipids from microglial cells."Experimental Neurology. 185. 220-231 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ohkubo N, Lee YD, Morishima A, Terashima T, Kikkawa S, Tohyama M, Sakanaka M, Tanaka J, Maeda N, Vitek MP, Mitsuda N: "Apolipoprotein E and Reelin ligands modulate tau phosphorylation through an apolipoprotein E receptor/disabled-1/glycogen synthase kinase-3beta cascade."FASEB Journal. 17・2. 295-297 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Morishima A, Ohkubo N, Maeda N, Miki T, Mitsuda N: "NFκB regulates plasma apolipoprotein A-I and HDL-cholesterol through inhibition of PPARα"Journal of Biological Chemistry. 278・40. 38188-38193 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Mori K, Yokoyama A, Yang L, Yang L, Maeda N, Mitsuda N, Tanaka J: "L-Serine-mediated release of apolipoprotein E and lipids from microglial cells."Experimental Neurology. 185・2. 220-231 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nobutaka Ohkubo, et al.: "Apolipoprotein-E and Reelin ligands modulate tau phosphorylation through an Apolipoprotein-E receptor/Disabled-l/Glycogen Synthase Kinase-3β cascade"FASEB Journal. Dec.18(Published on line). (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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