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Development of therapeutic strategy for Alzheimer's disease by targeting amyloid precursor protein C99

Research Project

Project/Area Number 23500445
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Neurochemistry/Neuropharmacology
Research InstitutionShiga University of Medical Science

Principal Investigator

NISHIMURA Masaki  滋賀医科大学, 分子神経科学研究センター, 准教授 (40322739)

Co-Investigator(Kenkyū-buntansha) MATSUO Akinori  滋賀医科大学, 分子神経科学研究センター, 助教 (20324585)
Project Period (FY) 2011 – 2013
Project Status Completed (Fiscal Year 2013)
Budget Amount *help
¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywordsアルツハイマー病 / アミロイドβ / ILEI / FAM3C / γセクレターゼ / 神経疾患 / βアミロイド / トランスジェニック・マウス / 認知症
Research Abstract

Accumulation of amyloid-b (Ab) in the brain underlies the pathogenesis of Alzheimer's disease (AD). Ab is produced by b- and g-secretase-mediated sequential proteolysis of Ab precursor protein (APP). Although g-secretase is a major target of therapeutic intervention, non-selective inhibition of its activity causes serious adverse effects due to blockade of Notch signaling. We have identified a secretory protein named ILEI as a negative regulator of Ab production. ILEI destabilized the b-secretase-cleaved APP C-terminal fragment, APP-C99, by binding to the g-secretase complex and interfering with its chaperone properties. Notch signaling and g-secretase activity were not affected by ILEI. We also show neuronal expression of ILEI and its reduction in the brains of AD patients. transgenic over expression of ILEI significantly reduced the brain Ab burden and ameliorates the memory deficit in AD model mice. ILEI may be a plausible target for the development of disease-modifying therapies.

Report

(4 results)
  • 2013 Annual Research Report   Final Research Report ( PDF )
  • 2012 Research-status Report
  • 2011 Research-status Report
  • Research Products

    (45 results)

All 2014 2013 2012 2011 Other

All Journal Article (18 results) (of which Peer Reviewed: 16 results) Presentation (17 results) (of which Invited: 1 results) Book (2 results) Remarks (4 results) Patent(Industrial Property Rights) (4 results) (of which Overseas: 2 results)

  • [Journal Article] The FAM3 superfamily member ILEI ameliorates Alzheimer's disease-like pathology by destabilizing the penultimate amyloid-beta precursor.2014

    • Author(s)
      Hasegawa, H., L. Liu, I. Tooyama, S. Murayama and M. Nishimura
    • Journal Title

      Nat Commun

      Volume: 5 Issue: 1 Pages: 3917-3917

    • DOI

      10.1038/ncomms4917

    • Related Report
      2013 Annual Research Report 2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] OCIAD2 activates γ-secretase to enhance amyloid β production by interacting with nicastrin.2014

    • Author(s)
      Han J, Jung S, Jang J, Kam TI, Choi H, Kim BJ, Nah J, Jo DG, Nakagawa T, Nishimura M, Jung YK.
    • Journal Title

      Cellular and Molecular Life Sciences

      Volume: 未定 Issue: 13 Pages: 2561-2576

    • DOI

      10.1007/s00018-013-1515-x

    • Related Report
      2013 Annual Research Report 2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Hyperpolarization-activated cyclic nucleotide gated channels : a potential molecular link between epileptic seizures and Aβ generation in Alzheimer's disease2012

    • Author(s)
      Saito Y, Inoue T, Zhu G, Kimura N, Okada M, Nishimura M, Kimura N, Murayama S, Kaneko S, Shigemoto R, Imoto1 K, Suzuki T
    • Journal Title

      Mol Neurodegener

      Volume: 7 Pages: 50-50

    • NAID

      120005133364

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Age-related modulation of γ-secretase activity in non-human primate brains2012

    • Author(s)
      Nishimura M, Nakamura S, Kimura N, Liu L, Suzuki T, Tooyama I
    • Journal Title

      J Neurochem

      Volume: 123(1) Pages: 21-28

    • NAID

      120005713696

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Membrane-microdomain localization of amyloid β-precursor protein (APP) C-terminal fragments is regulated by phosphorylation of the cytoplasmic Thr^<668> residue2012

    • Author(s)
      Matsushima T, Saito Y, Elliott JI, Iijima-Ando K, Nishimura M, Kimura N, Hata S, Yamamoto T, Nakaya T, Suzuki T
    • Journal Title

      J Biol Chem

      Volume: 287(23) Pages: 19715-19724

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] γセクレターゼ複合体に作用しAβ産生を制御する内在性タンパク質2012

    • Author(s)
      西村正樹
    • Journal Title

      Dementia Japan

      Volume: 26(1) Pages: 44-50

    • Related Report
      2013 Final Research Report 2011 Research-status Report
  • [Journal Article] Age-related modulation of γ-secretase activity in non-human primate brains2012

    • Author(s)
      Nishimura M
    • Journal Title

      J Neurochem

      Volume: 123 Issue: 1 Pages: 21-28

    • DOI

      10.1111/j.1471-4159.2012.07884.x

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Hyperpolarization-activated cyclic nucleotide gated channels: a potential molecular link between epileptic seizures and Abeta generation in Alzheimer's disease2012

    • Author(s)
      Saito Y
    • Journal Title

      Mol Neurodegener

      Volume: 7 Issue: 1 Pages: 50-50

    • DOI

      10.1186/1750-1326-7-50

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Membrane-microdomain localization of amyloid β-precursor protein (APP) C-terminal fragments is regulated by phosphorylation of the cytoplasmic Thr668 residue2012

    • Author(s)
      Matsushima T
    • Journal Title

      J Biol Chem

      Volume: 287 Issue: 23 Pages: 19715-19724

    • DOI

      10.1074/jbc.m111.334847

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Membrane-microdomain localization of amyloid β-precursor protein (APP) C-terminal fragments is regulated by phosphorylation of the cytoplasmic Thr668 residue.2012

    • Author(s)
      Matsushima T, et al.
    • Journal Title

      Journal of Biological Chemistry

      Volume: 287

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] Human neural stem cells overexpressing choline acetyltransferase restore cognitive function of kainic acid-Induced learning and memory deficit animals.2012

    • Author(s)
      Park D, et al.
    • Journal Title

      Cell Transplantaion

      Volume: 21 Pages: 365-371

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] Human neural stem cells overexpressing choline acetyltransferase restore cognition in rat model of cognitive dysfunction.2012

    • Author(s)
      Park D, et al.
    • Journal Title

      Experimental Neurology

      Volume: 234 Pages: 521-526

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] Potent amyloidogenicity and pathogenicity of Aβ432011

    • Author(s)
      Saito T, Suemoto T, Brouwers N, Sleegers K, Funamoto S, Mihira N, Matsuba Y, Yamada K, Nilsson P, Takano J, Nishimura M, Iwata N, Van Broeckhoven C, Ihara Y, Saido TC
    • Journal Title

      Nat Neurosci

      Volume: 14(8) Pages: 1023-1032

    • NAID

      120006985066

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Alternative processing of γ-secretase substrates in common forms of mild cognitive impairment and Alzheimer's disease : Evidence for γ-secretase dysfunction2011

    • Author(s)
      Hata S, Fujishige S, Araki Y, Taniguchi M, Urakami K, Peskind E, Akatsu H, Araseki M, Yamamoto K, Martins RN, Maeda M, Nishimura M, Levey A, Chung KA, Montine T, Leverenz J, Fagan A, Goate A, Bateman R, Holtzman DM, Yamamoto T, Nakaya N, Gandy S, Suzuki T
    • Journal Title

      Ann Neurol

      Volume: 69(6) Pages: 1026-1031

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Nuclear choline acetyltransferase activates transcription of a high-affinity choline transporter2011

    • Author(s)
      Matsuo A, Bellier JP, Nishimura M, Yasuhara O, Saito N, Kimura H
    • Journal Title

      J Biol Chem

      Volume: 286(7) Pages: 5836-5845

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] アルツハイマー病に対するメマンチン治療2011

    • Author(s)
      西村正樹
    • Journal Title

      医事新報

      Volume: 4537 Pages: 62-63

    • Related Report
      2013 Final Research Report
  • [Journal Article] Potent amyloidogenicity and pathogenicity of Aβ432011

    • Author(s)
      Takashi Saito, Takahiro Suemoto, Nathalie Brouwers, Kristel Sleegers, Satoru Funamoto, Naomi Mihira, Yukio Matsuba, Kazuyuki Yamada, Per Nilsson, Jiro Takano, Masaki Nishimura, Nobuhisa Iwata, Christine Van Broeckhoven, Yasuo Ihara, Takaomi C Saido
    • Journal Title

      Nature Neuroscience

      Volume: 14 Issue: 8 Pages: 1023-1032

    • DOI

      10.1038/nn.2858

    • NAID

      120006985066

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] Alternative processing of γ-secretase substrates in common forms of mild cognitive impairment and Alzheimer's disease : evidence for γ-secretase dysfunction2011

    • Author(s)
      Hata S
    • Journal Title

      Ann.Neurol.

      Volume: 69 Issue: 6 Pages: 1026-1031

    • DOI

      10.1002/ana.22343

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Presentation] p24α2 interacts with γ-secretase complex at presynaptic terminals2014

    • Author(s)
      Nishimura M, Liu L, Fujino K
    • Organizer
      Alzheimer's Association International Conference 2014
    • Place of Presentation
      Copenhagen
    • Related Report
      2013 Final Research Report
  • [Presentation] Expression of p24α2 in mammalian brain2014

    • Author(s)
      Nishimura M, Liu L
    • Organizer
      Experimental Biology 2014
    • Place of Presentation
      San Diego
    • Related Report
      2013 Final Research Report
  • [Presentation] ILEI はアルツハイマー病モデルマウスのアミロイド沈着と記憶障害を軽減させる2014

    • Author(s)
      劉磊, 長谷川浩史, 遠山育夫, 村山繁雄, 西村正樹
    • Organizer
      第33回日本認知症学会
    • Place of Presentation
      横浜
    • Related Report
      2013 Final Research Report
  • [Presentation] ILEI はAPP-C99 を不安定化することによりアミロイドβ産生を減少させる2014

    • Author(s)
      劉磊, 長谷川浩史, 遠山育夫, 村山繁雄, 西村正樹
    • Organizer
      第37回日本神経科学会
    • Place of Presentation
      横浜
    • Related Report
      2013 Final Research Report
  • [Presentation] p24α2 interacts with γ-secretase complex at presynaptic terminals.2014

    • Author(s)
      Nishimura M, Liu L, Fujino K.
    • Organizer
      Alzheimer’s Association International Conference 2014
    • Place of Presentation
      Copenhagen、デンマーク王国
    • Related Report
      2013 Annual Research Report
  • [Presentation] Expression of p24α2 in mammalian brain.2014

    • Author(s)
      Nishimura M, Lei Liu.
    • Organizer
      Experimental Biology 2014
    • Place of Presentation
      San Diego、アメリカ合衆国
    • Related Report
      2013 Annual Research Report
  • [Presentation] Modulation of Aβ42 production2013

    • Author(s)
      Nishimura M
    • Organizer
      11th World Congress of Biological Psychiatry
    • Place of Presentation
      Kyoto
    • Related Report
      2013 Final Research Report
  • [Presentation] Modulation of Aβ42 production.2013

    • Author(s)
      Nishimura M.
    • Organizer
      11th World Congress of Biological Psychiatry
    • Place of Presentation
      Kyoto
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] γセクレターゼ活性阻害タンパク質p24α2のシナプス局在2013

    • Author(s)
      劉 磊、西村正樹
    • Organizer
      日本認知症学会
    • Place of Presentation
      長野県松本市
    • Related Report
      2013 Annual Research Report
  • [Presentation] Age-related modulation of γ-secretase activity in monkey brains2012

    • Author(s)
      Nishimura M, Nakamura S, Kimura N, Liu L, Suzuki T, Tooyama I
    • Organizer
      Alzheimer's Association International Conference 2012
    • Place of Presentation
      Vancouver
    • Related Report
      2013 Final Research Report
  • [Presentation] Membrane microdomain localization of APP C-terminal fragments regulated by phosphorylation at cytoplasmic Thr668 residue2012

    • Author(s)
      Matsushima T, Saito Y, Nishimura M, Kimura N, Hata S, Suzuki T
    • Organizer
      Alzheimer's Association International Conference 2012
    • Place of Presentation
      Vancouver
    • Related Report
      2013 Final Research Report
  • [Presentation] 加齢に伴うカニクイザル脳γセクレターゼ活性の修飾 : Aβ42 産生比の増加2012

    • Author(s)
      西村正樹, 劉磊, 中村紳一朗, 木村展之, 鈴木利治, 遠山育夫
    • Organizer
      第31回日本認知症学会
    • Place of Presentation
      つくば
    • Related Report
      2013 Final Research Report
  • [Presentation] Age-related modulation of γ-secretase activity in monkey brains.2012

    • Author(s)
      Nishimura M, Nakamura S, Kimura N, Liu L, Suzuki T, Tooyama I.
    • Organizer
      Alzheimer’s Association International Conference 2012
    • Place of Presentation
      Vancouver, Canada
    • Related Report
      2012 Research-status Report
  • [Presentation] Interaction of p24α2 with γ-secretase complex attenuates γ-cleavage of APP2011

    • Author(s)
      Nishimura M, Liu L, Hasegawa H
    • Organizer
      Alzheimer's Association International Conference 2011
    • Place of Presentation
      Paris
    • Related Report
      2013 Final Research Report
  • [Presentation] Nuclear choline acetyltransferase activates transcription of a high-affinity choline transporter2011

    • Author(s)
      Matsuo A, Bellier JP, Nishimura M, Yasuhara O, Saito N, Kimura H
    • Organizer
      The 8th IBRO World Congress of Neuroscience
    • Place of Presentation
      Florence
    • Related Report
      2013 Final Research Report
  • [Presentation] Interaction of p24α2 with γ-secretase complex attenuates γ-cleavage of APP.2011

    • Author(s)
      Nishimura M, et al.
    • Organizer
      Alzheimer’s Association International Conference 2011
    • Place of Presentation
      Paris
    • Related Report
      2011 Research-status Report
  • [Presentation] Nuclear choline acetyltransferase activates transcription of a high-affinity choline transporter.2011

    • Author(s)
      Matsuo A, et al.
    • Organizer
      The 8th IBRO World Congress of Neuroscience
    • Place of Presentation
      Florence
    • Related Report
      2011 Research-status Report
  • [Book] タンパク質発現解析-免疫組織化学法に法補的な手法-. 「組織細胞化学2014」2014

    • Author(s)
      西村正樹
    • Publisher
      日本組織細胞化学会(印刷中)
    • Related Report
      2013 Final Research Report
  • [Book] 日本臨床増刊号認知症学(上)-その解明と治療の最新知見-2011

    • Author(s)
      西村正樹. Nicastrin
    • Publisher
      日本臨床社
    • Related Report
      2013 Final Research Report
  • [Remarks] ホームページ

    • URL

      http://ben.shiga-med.ac.jp/~hqmnran/index_1.html

    • Related Report
      2013 Final Research Report
  • [Remarks] 滋賀医科大学神経難病研究推進機構分子神経科学研究センター神経難病病因学分野

    • URL

      http://ben.shiga-med.ac.jp/~hqmnran/index_1.html

    • Related Report
      2013 Annual Research Report
  • [Remarks] 滋賀医科大学神経難病研究推進機構分子神経科学研究センター神経難病病因学分野

    • URL

      http://ben.shiga-med.ac.jp/~hqmnran/index_1.html

    • Related Report
      2012 Research-status Report
  • [Remarks]

    • URL

      http://ben.shiga-med.ac.jp/~hqmnran/index_1.html

    • Related Report
      2011 Research-status Report
  • [Patent(Industrial Property Rights)] アミロイドβタンパク質が異常に蓄積する疾患の治療及び/又は予防用の医薬組成物2013

    • Inventor(s)
      西村正樹
    • Industrial Property Rights Holder
      滋賀医科大学
    • Filing Date
      2013-12-13
    • Related Report
      2013 Final Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] アミロイドβタンパク質が異常に蓄積する疾患の治療及び/又は予防用の医薬組成物2013

    • Inventor(s)
      西村正樹
    • Industrial Property Rights Holder
      滋賀医科大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2013-12-13
    • Related Report
      2013 Annual Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] アミロイドβタンパク質が異常に蓄積する疾患の治療及び/又は予防用の医薬組成物2012

    • Inventor(s)
      西村正樹
    • Industrial Property Rights Holder
      滋賀医科大学
    • Industrial Property Number
      2012-277068
    • Filing Date
      2012-12-19
    • Related Report
      2013 Final Research Report
  • [Patent(Industrial Property Rights)] アミロイドβタンパク質が異常に蓄積する疾患の治療及び/又は予防用の医薬組成物2012

    • Inventor(s)
      西村正樹
    • Industrial Property Rights Holder
      滋賀医科大学
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2012-277068
    • Filing Date
      2012-12-19
    • Related Report
      2012 Research-status Report

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Published: 2011-08-05   Modified: 2019-07-29  

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