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Influence of membrane lipid metabolism on cerebral amyloid deposition and neurodegeneration.

Research Project

Project/Area Number 13480250
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Nerve anatomy/Neuropathology
Research InstitutionGunma University

Principal Investigator

YAMAGUCHI Haruyasu  Gunma University, School of Health Sciences, Professor, 医学部, 教授 (00158114)

Co-Investigator(Kenkyū-buntansha) SASAKI Atsushi  Gunma University, School of Medicine, Assistant Professor, 医学部, 講師 (80225862)
YANAGISAWA Katsuhiko  National Institute for Longevity Science, Director, 痴呆疾患研究部, 部長 (10230260)
C.FUJITA Shinobu  Mitsubishi Kasei Life Science Institute, Senior Researcher, 生命科学研究所, 主任研究員
浦上 克哉  鳥取大学, 医学部, 教授 (30213507)
Project Period (FY) 2001 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥15,000,000 (Direct Cost: ¥15,000,000)
Fiscal Year 2003: ¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2002: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2001: ¥8,500,000 (Direct Cost: ¥8,500,000)
KeywordsAlzheimer's disease / amyloid / dementia / ApoE / animal model / raft
Research Abstract

We examined the ultrastructure of rafts in rat brain tissue by pre-embedding immunoelectron microscopy using flotillin-1 antibody, which is biochemical marker of lipid rafts, and BCθ, which is nicked and biotinylated θ-toxin, and binds to membrane cholesterol of rafts. Flotillin-1-and BCθ-labeled areas were patchy and prominent on the plasma membranes of small processes and synapses in the neuropil. The size of flotillin-1 labeling was 40 to 200nm.In addition, the membrane of lysosome and Golgi apparatus were frequently labeled for flotillin-1 with a patchy pattern. Flotillin-1 and BCθ were mostly colocalized in double immunolabeling on a part of the plasma membranes of small processes and secondary lysosome membranes. We first indicate that flotillin-1 localizes to BCθ-positive cholesterol-rich membrane microdomains in vivo, and that flotillin-1 and BCθ could be an ultrastructural rafts marker in neural tissue. We also examined the relation between lipid raft and cerebral β-amyloid deposition in the Tg2576 transgenic mouse.
Moreover, we found a striking difference in the distribution of membrane cholesterol. ApoE4 knock-in mice showed an approximately 2-fold increase in exofacial leaflet cholesterol compared with apoE3 knock-in mice and wild-type mice.

Report

(4 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (30 results)

All Other

All Publications (30 results)

  • [Publications] Yamaguchi H: "Alzheimer β amyloid deposition enhanced by ApoE ε4 gene, precedes neurofibrillary pathology in the frontal association cortex of non-demented senior subjects."J Neuropathol Exp Neurol. 60. 731-739 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kokubo H: "Ultrastructural localization of flotillin-1 to cholesterol-rich membrane microdomains, rafts, in rat brain tissue"Brain Res. 965. 83-90 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sai X: "Endoplasmic reticulum stress-inducible protein, Herp, enhances presenilin-mediated generation of amyloid β-protein"J Biol Chem. 277. 12915-12920 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Mori T: "Increased vulnerability to focal ischemic brain injury in human apolippoprotein E4 knock-in mice"J.Neuropathol.Exp.Neurol. 62. 280-291 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hayashi H: "Choleterol is increased in the expfacial leaflet of synaptic plasma membranes of human apolipoprotein E4 knock-in mice"NeuroReport. 13. 383-386 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Takahashi RH: "Intraneuronal Alzneimer Abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology"Am J Pathol. 161. 1869-1879 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yamaguchi H: "Alzheimer β amyloid deposition enhanced by ApoE ε4 gene, precedes neurofibrillary pathology in the frontal association cortex of non-demented senior subjects."J Neuropathol Exp Neurol. 60. 731-739 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Takahashi RH: "Intraneuronal Alzheimer Aβ42 accumulates in multivesicular bodies and is associated with synaptic pathology."Am J Pathol. 161. 1869-1879 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kokubo H: "Ultrastructural localization of flotillin-1 to cholesterol-rich membrane microdomains, rafts, in rat brain tissue."Brain Res. 965. 83-90 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sai X: "Endoplasmic reticulum stress-inducible protein, Herp, enhances presenilin-mediated generation of amyloid β-protein."J Biol Chem. 277. 12915-12920 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Mori T: "Increased vulnerability to focal ischemic brain injury in human apolippoprotein E4 knock-in mice."J.Neuropathol.Exp.Neurol.. 62. 280-291 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hayashi H: "Cholesterol is increased in the exofacial leaflet of synaptic plasma membranes of human apolipoprotein E4 knock-in mice."NeuroReport. 13. 383-386 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kobuku H et al.: "Ultrastructural localization of flotillin-1 to cholesterol-rich membrane microdomains, rafts, in rat brain tissue"Brain Res. 965. 83-90 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Sasaki A et al.: "Antiserum against human glucose transporter 5 is highly specific for microglia among cells of the mononuclear phagocyte system"Neurosci Lett. 338. 17-20 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kobayashi M et al.: "Phosphorylation state of tau in the hippocampus of apolipoprotein E4 and E3 knock-in mice"Neuroreport. Apr15;14(5). 699-702 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kawauchi D et al.: "MuSC is involved in regulating axonal fasciculation of mouse primary vestibular afferents"Eur J Neurosci. 18(8). 2244-2252 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Sai X et al.: "The ubiquitin-like domain of Herp is involved in Herp degradation, but not necessary for its enhancement of amyloid beta-protein generation"FEBS Lett. 553(1-2). 151-156 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yanagisawa K et al.: "Cholesterol and Aβ aggregation"Pharmacopsychiatry. Sep;36 Suppl 2:. S127-S129 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Sun X et al.: "Lithium inhibits amyloid secretion in COS7 cells transfected with amyloid precursor protein C100"Neurosci Lett. 321巻. 61-64 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Thal DR et al.: "Two types of sporadic cerebral amyloid angiopathy"J Neuropathol Exp Neurol. 61巻. 282-293 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tanemura K et al.: "Neurodegeneration with tau accumulation in a transgenic mouse expressing V337M human tau"J Neurosci. 22巻. 133-141 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takahashi RH et al.: "Intraneuronal Alzneimer Aβ42 accumulates in multivesicular bodies and is associated with synaptic pathology"Am J Pathol. 161巻. 1869-1879 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Sai X et al.: "Endoplasmic reticulum stress-inducible protein, Herp, enhances presenilin-mediated generation of amyloid β-protein"J Biol Chem. 277巻. 12915-12920 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Xia X et al.: "The aspartate-257 of presenilin 1 is indispensable for mouse development and production of β-amyloid peptides through β-catenin-independent mechanisms"Proc Natl Acad Sci USA. 99巻. 8760-8765 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yamaguchi H et al.: "Alzheimer β amyloid deposition, with is hastened by ApoE ε4 gene, precedes neurofibrillary pathology in the frontal association cortex of non-demented senior subjects."J Neuropathol Exp Neurol. 60巻. 731-739 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Oshima N et al.: "Accumulation of amyloid β-protein in the low-density membrane domain accurately reflects the extent of β-amyloid deposition in the brain"Am J Pathol. 158巻. 2209-2218 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tanemura K et al.: "Neurodegeneration with tau accumulation in a transgenic mouse expressing V337M human tau"J Neurosci. 22巻. 133-141 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Sun X et al.: "Intracellular Aβ is increaaed by okadaic acid exposure in transfected neuronal and non-neuronal cell lines"Neurobiol Aging. 23巻. 195-203 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Sai X et al.: "Endoplasmic reticulum stress-inducible protein, Herp, enhances presenilin-mediated generation of amyloid β-protein"J Biol Chem. (In press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Planel E et al.: "Inhibition of protein phosphatase 2A overrides tau protein kinase I/glycogen synthase kinase 3β and cyclin-dependent kinase 5 inhibition and results in tau hyperphosphorylation in the hippocampus of starved mouse"J Biol Chem. 276巻. 34298-34306 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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