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Molecular mechanisms underlying Alzheimer's neurodegeneration:implication for A βoligomer Ca^2+ channels

Research Project

Project/Area Number 23659449
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeMulti-year Fund
Research Field Neurology
Research InstitutionHirosaki University

Principal Investigator

MATSUBARA Etsuro  弘前大学, 医学(系)研究科(研究院), 准教授 (70219468)

Project Period (FY) 2011 – 2012
Project Status Completed (Fiscal Year 2012)
Budget Amount *help
¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2011: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
KeywordsAβオリゴマー / カルシウムチャンネル / シナプス / 神経細胞変性 / カルシウム
Research Abstract

The molecular mechanism of calcium (Ca^2+) homeostasis underlying immunotherapy targeting Aβ oligomers (AβOs) remains to be determined. We found that AβOs caused calcium (Ca^2+) overload in the cytosol of viable cells. The anti-AβO antibody 72D9afforded a near blockade of cytosolic Ca^2+ overload in cortical neurons obtained from either non-Tg or 3x Tg-AD mice, indicating that cytosolic Ca^2+ overload originates from extracellular Ca^2+. Neither N-methyl-D-aspartic acid (NMDA) anatagonists nor L-type voltage-dependent Ca^2+ channel (L-VDDC) blockers also attenuated them, suggesting that the impairment of membrane integrity was owing to AβO-depending action such as a pore formation for Ca^2+. Thus, in neurons, monoclonal 72D9 acts as a modulator of pathological Ca^2+ -homeostasis via specific control of extracellular AβOs.

Report

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

    (23 results)

All 2013 2012 2011 2009 2008 Other

All Journal Article (7 results) (of which Peer Reviewed: 6 results) Presentation (10 results) (of which Invited: 3 results) Book (2 results) Remarks (1 results) Patent(Industrial Property Rights) (3 results) (of which Overseas: 3 results)

  • [Journal Article] The Alzheimer Disease Genetics Consortium2013

    • Author(s)
      Miyashita A, Koike A, Jun G, Wang L-S, Takahashi S, Matsubara E, Kawarabayashi T, Shoji M, Tomita N, Arai H, Asada T, Harigaya Y, Ikeda M, Amari M, Hanyu H, Higuchi S, Ikeuchi T, Nishizawa M, Suga M, Kawase Y, Akatsu H, Kosaka K, Yamamoto T, Imagawa M, Hamaguchi T, Yamada M, Moriaha T, Takeda M, Takao T, Nakata K, Fujisawa Y, Sasaki K, Watanabe K, Nakashima K, Urakami K, Ooya T, Takahashi M, Yuzuhira T, Serikawa K, Yoshimoto S, Nakagawa R, Kim J-W, Ki C-S, Won H-H, Na DL, Seo SW, Mook-Jung I St. George-Hyslop P, Mayeux R, Hagines JL, Pericak-Vance MA, Yoshida M, Tokunaga K, Yamamoto K, Tsuji S, Kanazawa I, Ihara Y, Schellenburg GD, Farrer LA, Kuwano
    • Journal Title

      SORL1 is genetically associated with late-onset Alzheimer's disease in Japanease, Koreans and Caucasians.

      Volume: 8

    • Related Report
      2012 Final Research Report
  • [Journal Article] Sortilin is required for toxic action of Aβ oligomers (AβOs): Extracellular AβOs trigger apoptosis, and intraneuronal AβOs impair degradation pathways2012

    • Author(s)
      Ayumi Takamura
    • Journal Title

      Life Sciences

      Volume: 91 Issue: 23-24 Pages: 1177-1186

    • DOI

      10.1016/j.lfs.2012.04.038

    • Related Report
      2012 Annual Research Report 2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Molecular mechanism underlying Aβ immunotherapy: implications for the toxic action of Aβ oligomers.2012

    • Author(s)
      Matsubara E, Takamura A
    • Journal Title

      J Gerontol Geriat Res

      Volume: S2:001

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Molecular mechanism underlying Aβ immunotherapy: implications for the toxic action of Aβ oligomers2012

    • Author(s)
      Etsuro Matsubara
    • Journal Title

      Journal of Gerontology & Geriatric Research

      Volume: Speial Issue Issue: 02 Pages: 1-5

    • DOI

      10.4172/2167-7182.s2-001

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The Dissociation of Aβ from Lipoprotein in Cerebrospinal Fluid from Alzheimer's Disease accelerates Aβ42 assembly.2011

    • Author(s)
      Takamura A, Kawarabayashi T, Yokoseki T, Shibata M, Morishima-Kawashima M, Saito Y, Murayama S, Ihara Y, Abe K, Shoji M, Michikawa M, Matsubara E
    • Journal Title

      J Neurosci Res

      Volume: 89 Pages: 815-821

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Extracellular and intraneuronal HMW-AbetaOs represent a molecular basis of memory loss in Alzheimer's disease model mouse2011

    • Author(s)
      Takamura A, Okamoto Y, Kawarabayashi T, Yokoseki T, Shibata M, Mouri A, Nabeshima T, Sun H, Abe K, Urisu T, Yamamoto N, Shoji M, Yanagisawa K, Michikawa M, Matsubara E
    • Journal Title

      Mol Neurodegener

      Volume: 6 Issue: 1 Pages: 20-20

    • DOI

      10.1186/1750-1326-6-20

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Shoji M: Factors responsible forneurofibrillary tangles and neuronal cell losses in tauopathy.2011

    • Author(s)
      Wakasaya Y, Kawarabayashi T, Watanabe M, Yamamoto-Watanabe Y, Takamura A, Kurata T, Murakami T, Abe K, Yamada K, Wakabayashi K, Sasaki A, Westaway D, Hyslop PS, Matsubara E
    • Journal Title

      J Neurosci Res

      Volume: 89 Pages: 576-584

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Presentation] Aβ oligomer immunotherapy as a potential disease-modifying therapy for Alzheimer's disease2012

    • Author(s)
      Matsubara E
    • Organizer
      The 15th MNRC International Symposium
    • Place of Presentation
      Shiga
    • Year and Date
      2012-11-13
    • Related Report
      2012 Final Research Report
  • [Presentation] トッピックス徹底討論,免疫療法2012

    • Author(s)
      松原悦朗
    • Organizer
      第31回日本認知症学会
    • Place of Presentation
      つくば
    • Year and Date
      2012-10-28
    • Related Report
      2012 Final Research Report
  • [Presentation] アルツハイマー病の早期診断・治療のためのガイドラインに向けて:predromal AD, Pre-MCI, 生化学的、病理学的バックグラウンド2012

    • Author(s)
      松原悦朗
    • Organizer
      第31回日本認知症学会
    • Place of Presentation
      つくば
    • Year and Date
      2012-10-26
    • Related Report
      2012 Final Research Report
  • [Presentation] アルツハイマー病治療開発への道程:臨床医学から見た基礎研究の意義.認知症研究を知る若手研究者の集まり2011

    • Author(s)
      松原悦朗
    • Organizer
      日本認知症学会主催・基礎委員会企画
    • Place of Presentation
      大府
    • Year and Date
      2011-07-30
    • Related Report
      2012 Final Research Report
  • [Presentation] 抗体医療開発の現状.Aging Science Forum「アルツハイマー病研究のup-to-date」2011

    • Author(s)
      松原悦朗
    • Organizer
      第48回日本老年医学会学術集会
    • Place of Presentation
      東京
    • Year and Date
      2011-06-17
    • Related Report
      2012 Final Research Report
  • [Presentation] アルツハイマー病モデルマウスに対するメラトニンの効果2011

    • Author(s)
      松原悦朗
    • Organizer
      第11回日本抗加齢医学会
    • Place of Presentation
      京都
    • Year and Date
      2011-05-28
    • Related Report
      2012 Final Research Report
  • [Presentation] 認知症治療の最前線.日本内科学会東北地方会2011

    • Author(s)
      松原悦朗
    • Organizer
      第57回生涯教育講演会
    • Place of Presentation
      仙台
    • Year and Date
      2011-02-19
    • Related Report
      2012 Final Research Report
  • [Presentation] Aβ oligomer immunotherapy as a potential disease-modifying therapy for Alzheimer’s disease

    • Author(s)
      Etsuro Matsubara
    • Organizer
      The 15th MNRC International Symposium
    • Place of Presentation
      Shiga
    • Related Report
      2012 Annual Research Report
    • Invited
  • [Presentation] 生化学,病理学的バックグラウンド.シンポジウム2「アルツハイマー病の早期診断・治療のためのガイドラインに向けて:preclinical AD, pre-MCI」

    • Author(s)
      松原悦朗
    • Organizer
      第31回日本認知症学会学術集会
    • Place of Presentation
      つくば
    • Related Report
      2012 Annual Research Report
    • Invited
  • [Presentation] トッピックス徹底討論, 免疫療法

    • Author(s)
      松原悦朗
    • Organizer
      第31回日本認知症学会学術集会
    • Place of Presentation
      つくば
    • Related Report
      2012 Annual Research Report
    • Invited
  • [Book]2012

    • Author(s)
      Matsubara E
    • Publisher
      Lipoproteins and apolipoproteins in Alzheimer's disease (Kostner G, Frank S eds) Lipoprotein / Book
    • Related Report
      2012 Final Research Report
  • [Book] Lipoprotein-role in health and diseases2012

    • Author(s)
      Etsuro Matsubara
    • Total Pages
      758
    • Publisher
      InTech
    • Related Report
      2012 Annual Research Report
  • [Remarks]

    • URL

      http://www.h-shinnai.jp

    • Related Report
      2012 Final Research Report
  • [Patent(Industrial Property Rights)] Antibody specific binding to A Beta oligomer and the use.2009

    • Inventor(s)
      松原悦朗、柴田昌夫、達巳
    • Industrial Property Rights Holder
      イムナス・ファーマ株式会社、国立長寿医療研究センター
    • Filing Date
      2009-07-31
    • Related Report
      2012 Final Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] Antibodies that specifically bind to Aβ oligomers and uses thereof2009

    • Inventor(s)
      松原悦朗、柴田昌夫、達巳
    • Industrial Property Rights Holder
      イムナス・ファーマ株式会社、国立長寿医療研究センター
    • Filing Date
      2009-07-31
    • Related Report
      2012 Final Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] βオリゴマーに特異的に結合する抗体およびその利用2008

    • Inventor(s)
      松原悦朗、柴田昌夫、達巳
    • Industrial Property Rights Holder
      イムナス・ファーマ株式会社、国立長寿医療研究センター
    • Filing Date
      2008-10-17
    • Related Report
      2012 Final Research Report
    • Overseas

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

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