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Analysis of pathological phenotypes of familial Alzheimer's disease-associated gene mutations in presenilin.

Research Project

Project/Area Number 09672271
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Biological pharmacy
Research InstitutionRIKEN Brain Science Institute

Principal Investigator

SAIDO Takaomi C.  RIKEN Brain Scinece Institute, Laboratory for Proteolytic Neuroscience, Laboratory Head., 神経蛋白制御研究チーム, チームリーダー(研究職) (80205690)

Co-Investigator(Kenkyū-buntansha) MARUYAMA Kei  National Institute for Physiological Sciences and Graduate University for Advanc, 生理学研究所, 助教授 (30211577)
Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 1998: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1997: ¥1,800,000 (Direct Cost: ¥1,800,000)
KeywordsALZHEIMER'S DISEASE / PRESENILIN / beta-AMYLOID / SECRETASE
Research Abstract

Familial Alzheimer's disease is caused by mutations in several independent genes, among which presenilin mutations account for the majority of cases. Identification of pathological phenotypes of presenilin mutations would contribute to understanding the mechanism of other forms of Alzheimer's disease including sporadic Alzheimer's disease. We have discovered that the pathogenic mutations cause an increase in cellular production of 42mer beta-amyloid peptide, strongly supporting the role of beta-amyloid in Alzheimer's disease development. Furthermore, we identified a calcium-binding protein that interacts with presenilin in cells. This indicates that presenilin may influence cellular functions through influencing calcium-associated signal transduction and/or homeostasis.

Report

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

    (57 results)

All Other

All Publications (57 results)

  • [Publications] Tekirian,T.L.et al.: "Amino terminus heterogeneity of Parenchymal and Cerebraovascular β-amyloid deposits in aged human,canine,and polar bear brains." J.Neuropathol.Exp.Neurol.57. 76-94 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Oyama,F.et al.: "Mutant presenilin 2 transgenic mouse:Effect on an age-dependent increase of amyloid β-protein (Aβ) 42 in brain." J.Neurochem.71. 313-322 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Fautschy,S.A.et al.: "Microglial response to amyloid plaques in APP sw transgenic mice." Am.J.Pathol.152. 307-317 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Ono,Y.et al.: "Functional defects of a muscle-specific calpain,p94,caused by mutations associated with Limb-Girdle muscular dystrophy type 2A." J.Bilo.Chem.273. 17073-17078 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Tomita,T.et al.: "Molecular dissection of domains in mutant presenilin 2 that mediate overproduction of amyloidogenic forms of amyloid β peptides." J.Biol.Chem.273. 21153-21160 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Fautschy,S.A.et al.: "Protease inhibitor confusion with amyloid β-protein results in enhanced deposition and toxicity in rat brain." J.neurosci.18. 8311-8321 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Fox,J.E.B.et.al.: "Calpain:Pharmacology and Toxicology of a calcium-dependent cellular protease" Taylor & Francis.(Brisotol)(in press), (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Bloomgren, K.et.al.: "The calpain proteolytic system in neonatal hypoxic-ischemia." Ann.New York Acad.Sci.825. 104 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kuda, T.et.al.: "Reduction of plasma glutamyl aminopeptidase activity in sporadic Alzheimer's disease." Biochem.Biophys.Res.Commun.231. 526 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Tomita, T.et.al.: "The presenilin 2 mutation (N141I) linked to familial Alzheimer's disease (Volga German families) increases the secretion of amyloid beta protein ending at Abeta42(43)." Proc.Nat.Acad.Sci.USA.94. 2025 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Mann, D.M.A.et.al.: "Preferential Deposition of amyloid beta protein (Abeta) in the form of Abeta40 in Alzheimer's disease is associated with a gene dosage effect of the apolipoprotein E E4 allele." Neurosci.Lett.221. 81 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Mann, D.M.A.et.al.: "An intronic polymorphism in the presenilin-1 gene does not influence the amount or molecular form of the amyloid beta protein deposited in Alzheimer's disease." Neurosci.Lett.222. 57 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Saito, Y.et.al.: "Overexpression of a neuropeptide nociceptin/orphanin FQ precursor gene, N23K/N27K,induces neurite outgrowth in mouse NS20Y cells." J.Neurosci.Res.48. 397 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Saido, T.C.: "Alzheimer's disease as proteolytic disorders : Anabolism and catabolism of beta-amyloid." Neurobiol.Aging.19. S69 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Saido, T.C.et.al.: "Up-and down-regulation of calpain inhibitor polypeptide, calpastain, in postischemic hippocampus." Neurosci.Lett.227. 75 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Russo, C.et.al.: "Heterogeneity of water-soluble amyloid beta-peptide in Alzheimer's disease and Down's syndrome brains." FEBS Lett.409. 411 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yamazaki, T.et.al.: "Specific increase in amyloid beta-protein42 secretion ratio by calpain inhibition." Biochemistry. 36. 8377 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kouchi, Z.et.al.: "The restrictive proteolysis of alpha-fodrin to a 120 kDa fragment is not catalyzed by calpains during thymic apoptosis." Apoptosis. 2. 84 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yamazaki, M.et.al.: "Cytoplasmic processing of human profilaggrin by active mu-calpain." Biochem.Biophys.Res.Commun.235. 652 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Didier, M.et.al.: "Involvement of three glutamate receptor epsilon subunits in the formation of N-methyl-D-aspartate receptors mediating excitotoxicity in primary cultures of mouse cerebellar granule cells." Neuroscince. 78. 1129 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yan, S.D.et.al.: "ERAB : A novel intracellular amyloid-beta peptide binding protein which mediates neurotoxicity in Alzheimer's disease." Nature.389. 689 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Schoenwaelder, S.M.et.al.: "Distinct substrate specificities and functional roles for the 78 and 76 kDa forms of mu-calpain in human platelets." J.Biol.Chem.272. 24876 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Shin, R.-W.et.al.: "Amyloid beta-protein (Abeta) 1-40 but not Abeta1-42 contributes experimental formation of Alzheimer disease amyloid fibrils in rat brain." J.Neurosci.17. 8187 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Tekirian, T.L.et.al.: "Amino terminus heterogeneity of Parenchymal and Cerebrovascular beta-amyloid deposits in aged human, canine, and polar bear brains." J.Neuropathol.Exp.Neurol.57. 76 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Sorimachi, Y.et.al.: "Downregulation of calpastatin in rat heart after brief ischemia and reperfusion." J.Biochem.122. 743 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Inomata, M.et.al.: "Evidence for involvement of calpain in the cataractgenesis in Shumiya Cataract Rat." Biochim.Biophys.Acta.1362. 11 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Schmidt, M.L.et.al.: "Amyloid plaques in Guam ALS and Parkinsonism-dementia complex contain species of Abeta similar to those found in the amyloid plaques of Alzheimer's disease." Acta Neurophatol.(in press). (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Oyama, F.et.al.: "Mutant presenilin 2 transgenic mouse : Effect on an age-dependent increase of amyloid beta-protein (Abeta)42 in brain." J.Neurochem.71. 313 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Frautschy, S.A.et.al.: "Microglial response to amyloid plaques in APPsw transgenic mice." Am.J.Pathol.152. 307 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Tokuhiro, S.et.al.: "The presenilin 1 mutation (M146V) linked to familial Alzheimer's disease attenuates the neuronal differentiation of NTera 2 cells." Biochem.Biophys.Res.Commun. 244. 751 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Shinozaki, K.et.al.: "The presenilin 2 loop domain interacts with the mu-calpain C-terminal region." Int.J.Mol.Med.1. 797 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Sudoh, S.et.al.: "The presenilin 1 mutations linked to familial Alzheimer's disease elevate a production of N-terminally truncated Abeta42 variant.Abeta11-42, which is generated through distinct processing pathway from Abeta1-42." J.Neurochem.1535 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Funato, H.et.al.: "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 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kimura, Y.et.al.: "The involvement of calpain-dependent proteolysis of the tumor suppressor NF2 (merlin) in schwannomas and meningiomas." Nature Med.8. 915 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Ono, Y.et.al.: "Functional defects of a muscle-specific calpain, p94, caused by mutations associated with Limb-Girdle muscular dystrophy type 2A." J.Biol.Chem.273. 17073 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yamaguchi, H.et.al.: "Diffuse plaques associated with astroglial amyloid beta protein, possibly showing a disappearing stage of senile plaques." Acta Neuropathol.95. 217 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Meredith, J.Jr.et.al.: "Cleavage of the cytoplasmic domain of the integrin beta3 subunit during endothelial cell apoptosis." J.Biol.Chem.273. 19525 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Akiyama, H.et.al.: "Occurrence of the diffuse deposits with numerous amyloid beta-protein (Abeta)-containing glial cells in the cerebral cortex of patients with Alzhemer's disease." Glia. (in press). (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Tomita, T.et.al.: "Molecular dissection of domains in mutant presenilin 2 that mediate overproduction of amyloidogenic forms of amyloid beta peptides." J.Biol.Chem.273. 21153 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Frautschy, S.A.et.al.: "Protease inhibitor coinfusion with amyloid beta-protein results in enhanced deposition and toxicity in rat brain." J.Neurosci.18. 8311 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Hiwasa, T.et.al.: "Down-regulation of protein kinase C and enhanced TPA-induced neurite formation in DAN-transfected neuroblastoma cells." FEBS Lett.440. 25 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Ishidoh, K.et.al.: "Multiple processing of procathepsin L to cathepsin L in vivo." Biochem.Biophys.Res.Commun.252. 202 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kitagawa, K.et.al.: "Species differences in fodrin proteolysis in the ischemic brain." J.Neurosci.Res.(in press). (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Honda.T.et.al.: "Dual roles of proteasome in the metabolism of presenilin 1." J.Neurochem.72. 255 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Hosoda, R.et.al.: "Quantitation of modified amyloid beta peptides in Alzheimer disease and down syndrome brains" J.Neuropathol.Exp.Neurol.57. 1089 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yokota, M.et.al.: "Calpain inhibitor entrapped in liposome rescues ischemic neuronal damage." Brain research. (in press). (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Tekirian, T.L.et.al.: "Amino terminus heterogeneity of Parenchymal and Cerebraovascular β-amyloid deposits in aged human, canine, and polar bear brains." J.Neuropathol.Exp.Neurol.57. 76-94 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Oyama, F.et.al.: "Mutant presenilin 2 transgenic mouse:Effect on an age-dependent increase of amyloid β-protein(Aβ)42 in brain." J.Neurochem.71. 313-322 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Fautschy, S.A.et.al.: "Microglial response to amyloid plaques in APPsw transgenic mice." Am.J.Pathol.152. 307-317 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Ono, Y.et.al.: "Functional defects of a muscle-specific calpain, p94, caused by mutations associated with Limb-Girdle muscular dystrophy type 2A." J.Bilo.Chem.273. 17073-17078 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Tomita, T.et.al.: "Molecular dissection of domains in mutant presenilin 2 that mediate overproduction of amyloidogenic forms of amyloid β peptides." J.Biol.Chem.273. 21153-21160 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Fautschy, S.A.et.al.: "Protease inhibitor confusion with amyloid β-protein results in enhanced deposition and toxicity in rat brain." J.neurosci.18. 8311-8321 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Fox, J.E.B.et.al.: "Calpain:Pharmacology and Toxicology of a calcium-dependent cellular protease(in press.)" Taylor & Francis.(Brisotol), (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Tomita,T.et al.: "Presenilin 2 mutation linked to familial AD inceases the secretion of AB42" Proc.Nath.Acad.Sci.94. 2025-2030 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Mann DMA et al: "An intronic polymorphism in the presemilin lgene does not influonce the amount of amylosd B protein" Neurosci.Lett. 222. 57-60 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Russo,C.et al.: "Meterogeneity of mater-solnble anyloid B-peptide in Alzheimer's disease" FEBS Lett.409. 411-416 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Saito T.C: "Alzheimer's disease as proteolytic disorders" Newwbiol Aging. (印刷中). (1998)

    • Related Report
      1997 Annual Research Report

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

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