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Molecular mechanisms of BACE1 dysregulation and synaptic degeneration in Alzheimer's disease

Research Project

Project/Area Number 16K09688
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Neurology
Research InstitutionNational Center of Neurology and Psychiatry

Principal Investigator

ARAKI WATARU  国立研究開発法人国立精神・神経医療研究センター, 神経研究所 疾病研究第六部, 研究員 (60311429)

Research Collaborator LAKSHMANA MADEPALI  Torrey Pines Institute for Molecular Studies, Associate Member
KAMETANI FUYUKI  東京都医学総合研究所, 研究員
TAMAOKA AKIRA  筑波大学, 人間総合科学研究科, 教授
TANIGUCHI KAORI  国立精神・神経医療研究センター, 神経研究所 疾病研究第六部, 流動研究員
YAMAMOTO FUMIKO  国立精神・神経医療研究センター, 神経研究所 疾病研究第六部, 研究生
ARAI TAKUYA  国立精神・神経医療研究センター, 神経研究所 疾病研究第六部, 科研費研究助手
YANG JINWEI  (株)常磐植物化学研究所
KONISHI YOSHIHIRO  鳥取医療センター, 臨床研究部長
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywordsアミロイドβ / アルツハイマー病 / 認知症 / シナプス / オリゴマー / βセクレターゼ / アルツハイマー / βアミロイド
Outline of Final Research Achievements

We investigated the mechanisms underlying the synaptic degeneration induced by amyloid β-protein (Aβ) oligomers and those by which Aβ production system including β-secretase is regulated.In primary neurons treated with Aβ oligomers, several presynaptic and postsynaptic proteins were abnormally dislocated, and Aβ was co-localized with two specific receptors on the surface of neuritic processes. These findings are important for elucidating the basis of the synaptic pathology in Alzheimer’s disease. In addition, we found that facilitation of the autophagy-lysosomal pathway has dual, but opposite, effects on the process of Aβ production.

Academic Significance and Societal Importance of the Research Achievements

アミロイドβタンパク質(Aβ)の可溶性集合体であるAβオリゴマーは、アルツハイマー病(AD)の病態の引金と考えられており、ADのシナプス変性に密接に関与している。Aβオリゴマーがシナプス変性を引き起こす分子機序は未解明であり、治療開発上、重要な課題である。本研究において、培養神経細胞モデルを用いた実験により、Aβオリゴマーが特定の受容体に結合することで、シナプスタンパク質の異常局在を含めたシナプスの攪乱を誘起することが示唆された。この知見は、ADのシナプス病態の実体解明に重要なものといえる。また、オートファジー・リソソーム系とAβの産生プロセスの関連性についても新知見を見出した。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (19 results)

All 2019 2018 2017 2016 Other

All Int'l Joint Research (3 results) Journal Article (5 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 5 results,  Open Access: 4 results,  Acknowledgement Compliant: 3 results) Presentation (7 results) (of which Int'l Joint Research: 1 results) Book (1 results) Remarks (3 results)

  • [Int'l Joint Research] Torrey Pines Inst for Mol Studies(米国)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] Torrey Pines Inst for Mol Studies(米国)

    • Related Report
      2017 Research-status Report
  • [Int'l Joint Research] Torrey Pines Inst for Mol Studies(米国)

    • Related Report
      2016 Research-status Report
  • [Journal Article] TFEB-mediated Enhancement of the Autophagy-lysosomal Pathway Dually Modulates the Process of Amyloid β-Protein Generation in Neurons.2019

    • Author(s)
      Yamamoto F, Taniguchi K, Mamada N, Tamaoka A, Kametani F, Lakshmana MK, Araki W.
    • Journal Title

      Neuroscience. 2

      Volume: 402 Pages: 11-22

    • DOI

      10.1016/j.neuroscience.2019.01.010

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Mitochondoria are devoid of amyloid beta-protein (Abeta)-producing secretases: Evidence for unlikely occurrence within mitochondria of Abeta generation from amyloid precursor protein.2017

    • Author(s)
      Naomi Mamada, Daisuke Tanokashira, Kazuhiro Ishii, Akira Tamaoka, Wataru Araki
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 486 Issue: 2 Pages: 321-328

    • DOI

      10.1016/j.bbrc.2017.03.035

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Reversibility of Aβ oligomer neurotoxicity2017

    • Author(s)
      Araki Wataru
    • Journal Title

      Oncotarget

      Volume: 8 Issue: 31 Pages: 50335-50336

    • DOI

      10.18632/oncotarget.19083

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The neurotoxicity of amyloid β-protein oligomers is reversible in a primary neuron model.2017

    • Author(s)
      Tanokashira D, Mamada N, Yamamoto F, Taniguchi K, Tamaoka A, Lakshmana MK, Araki W
    • Journal Title

      Mol Brain

      Volume: 10 Issue: 1 Pages: 4-4

    • DOI

      10.1186/s13041-016-0284-5

    • NAID

      120007135045

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Post-translational regulation of the β-secretase BACE12016

    • Author(s)
      Araki W
    • Journal Title

      Brain Research Bulletin

      Volume: 未定 Pages: 170-177

    • DOI

      10.1016/j.brainresbull.2016.04.009

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Presentation] Enhancement of the autophagy-lysosomal pathway modulates the process of amyloid β-protein generation2018

    • Author(s)
      Araki W, Yamamoto F, Taniguchi K, Mamada N, Tamaoka A, Kametani F, Lakashmana MK
    • Organizer
      18th World Congress of Basic and Clinical Pharmacology
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Enhancement of the autophagy-lysosomal pathway modulates the process of beta-amyloid generation2018

    • Author(s)
      Yamamoto F, Taniguchi K, Mamada N, Tamaoka A, Kametani F, Lakashmana MK, Araki W
    • Organizer
      第59回日本神経学会学術大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] オートファジー-リソソーム経路の促進のアミロイドβタンパク質産生過程への影響2017

    • Author(s)
      山本詞子,谷口香織,儘田直美,玉岡 晃,Madepalli K. Lakshmana,荒木 亘
    • Organizer
      第36回日本認知症学会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] Soluble Aβ oligomers induce disorganization of synapses in primary cultured neurons.2017

    • Author(s)
      Taniguchi K, Yamamoto F, Mamada N, Tamaoka A, Araki W
    • Organizer
      ConBio2017
    • Related Report
      2017 Research-status Report
  • [Presentation] The reversibility of the neurotoxicity induced by amyloid β-protein oligomers.2017

    • Author(s)
      Araki W, Tanokashira D, Mamada N, Yamamoto F, Taniguchi K, Tamaoka A, Lakshmana MK
    • Organizer
      第90回日本薬理学会年会
    • Place of Presentation
      長崎ブリックホール
    • Related Report
      2016 Research-status Report
  • [Presentation] The neurotoxicity of amyloid β-protein oligomers is reversible in nature.2016

    • Author(s)
      Araki W, Tanokashira D, Mamada N, Yamamoto F, Tamaoka A, Lakshmana MK
    • Organizer
      第39回日本神経科学大会
    • Place of Presentation
      パシフィコ横浜
    • Related Report
      2016 Research-status Report
  • [Presentation] Amyloid beta oligomers induce BACE1 augmentation in the neuritic compartment of neurons.2016

    • Author(s)
      Mamada N, Araki W, Tanokashira D, Kametani F, Tamaoka A
    • Organizer
      第57回日本神経学会学術大会
    • Place of Presentation
      神戸コンベンションセンター
    • Related Report
      2016 Research-status Report
  • [Book] アルツハイマー病 発症メカニズムと新規診断法・創薬・治療開発2018

    • Author(s)
      荒木亘,荒木由美子
    • Total Pages
      7
    • Publisher
      エヌ・ティー・エス
    • Related Report
      2018 Annual Research Report
  • [Remarks] 国立精神・神経医療研究センター神経研究所 疾病研究第6部

    • URL

      https://www.ncnp.go.jp/nin/guide/r6/index.html

    • Related Report
      2018 Annual Research Report
  • [Remarks] 国立精神・神経医療研究センター神経研究所 疾病研究第6部 第1研究室

    • URL

      http://www.ncnp.go.jp/nin/guide/r6/index-lab1.html

    • Related Report
      2017 Research-status Report
  • [Remarks] 国立精神・神経医療研究センター神経研究所 疾病研究第6部 第1研究室

    • URL

      http://www.ncnp.go.jp/nin/guide/r6/index-lab1.html

    • Related Report
      2016 Research-status Report

URL: 

Published: 2016-04-21   Modified: 2022-02-21  

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