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Identification of novel mechanisms of alcohol-related dementia

Research Project

Project/Area Number 18KK0258
Research Category

Fund for the Promotion of Joint International Research (Fostering Joint International Research (B))

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 57:Oral science and related fields
Research InstitutionNiigata University

Principal Investigator

Terunuma Miho  新潟大学, 医歯学系, 教授 (50615739)

Co-Investigator(Kenkyū-buntansha) 岸川 咲吏  福岡歯科大学, 口腔歯学部, 助教 (50781358)
飯田 和泉 (渡辺和泉)  新潟大学, 医歯学系, 助教 (80751031)
Project Period (FY) 2018-10-09 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000)
Fiscal Year 2021: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2020: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2019: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2018: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
Keywordsアストロサイト / アルツハイマー病 / アルコール / 認知機能 / アンモニア
Outline of Final Research Achievements

Chronic alcohol consumption can lead to the development of hyperammonemia due to liver dysfunction. We identified that liver failure-associated hyperammonemia induces neuroinflammation which can be described by the increased number of reactive astrocytes in the brain. We also identified that ammonia stimulation induces the production of amyloid beta, a critical initiator that triggers the progression of Alzheimer’s disease. Using primary cultured astrocytes prepared from rat embryo, we found the mechanisms of amyloid beta production; ammonia enhances amyloid precursor protein (APP) endocytosis from the plasma membrane, induces transportation of APP to the endoplasmic reticulum, where two enzymes cleave APP to generate amyloid beta peptides. We reported these mechanisms as a novel mechanism driving Alzheimer’s disease.

Academic Significance and Societal Importance of the Research Achievements

アミロイドβはアルツハイマー病の原因因子として長年注目されてきているが、神経細胞が産生し、細胞外に排出することで脳内に蓄積され、それが病理学的所見として観察されていると考えられてきた。研究代表者が本研究で見出したのは、脳内で最も数が多いグリア細胞であるアストロサイトがアミロイドβを産生する機構であり、新規の病態発症機序と考えられる。本研究での高アンモニア血症によるアルツハイマー病の発症の可能性を示す研究データは、日常生活においても高タンパク食の食事などでも起こり得る高アンモニア血症とアルツハイマー病との関連性を示すものであり、社会的意義が大きいと考える。

Report

(5 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (35 results)

All 2022 2021 2020 2019 2018 Other

All Int'l Joint Research (4 results) Journal Article (5 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 4 results,  Open Access: 4 results) Presentation (23 results) (of which Int'l Joint Research: 6 results,  Invited: 1 results) Remarks (3 results)

  • [Int'l Joint Research] タフツ大学(米国)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] タフツ大学(米国)

    • Related Report
      2020 Research-status Report
  • [Int'l Joint Research] タフツ大学(米国)

    • Related Report
      2019 Research-status Report
  • [Int'l Joint Research] タフツ大学(米国)

    • Related Report
      2018 Research-status Report
  • [Journal Article] Ammonia induces amyloidogenesis in astrocytes by promoting amyloid precursor protein translocation into the endoplasmic reticulum2022

    • Author(s)
      Komatsu Ayaka、Iida Izumi、Nasu Yusuke、Ito Genki、Harada Fumiko、Kishikawa Sari、Moss Stephen J.、Maeda Takeyasu、Terunuma Miho
    • Journal Title

      Journal of Biological Chemistry

      Volume: 298 Issue: 5 Pages: 101933-101933

    • DOI

      10.1016/j.jbc.2022.101933

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Direct Interaction of PP2A Phosphatase with GABAB Receptors Alters Functional Signaling.2020

    • Author(s)
      Li X, Terunuma M, Deeb TG, Wiseman S, Pangalos MN, Nairn AC, Moss SJ, Slesinger PA.
    • Journal Title

      Journal of Neuroscience

      Volume: 40(14) Issue: 14 Pages: 2808-2816

    • DOI

      10.1523/jneurosci.2654-19.2020

    • Related Report
      2020 Research-status Report 2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Sustained laryngeal transient receptor potential vanilloid 1 activation inhibits mechanically induced swallowing in anesthetized rats.2020

    • Author(s)
      Yoshihara M, Tsujimura T, Suzuki T, Nagoya K, Shiraishi N, Magara J, Terunuma M, Inoue M.
    • Journal Title

      Am J Physiol Gastrointest Liver Physiol.

      Volume: 319 Issue: 3 Pages: 412-419

    • DOI

      10.1152/ajpgi.00082.2020

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Drug-induced naive iPS cells exhibit better performance than primed iPS cells with respect to the ability to differentiate into pancreatic β-cell lineage2020

    • Author(s)
      Kiyokawa Y, Sato M, Noguchi H, Inada E, Iwase Y, Kubota N, Sawami T, Terunuma M, Maeda T, Hayasaki H, Saitoh I
    • Journal Title

      Journal of Clinical Medicine

      Volume: 9 Issue: 9 Pages: 2838-2838

    • DOI

      10.3390/jcm9092838

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Diversity of structure and function of GABA<sub>B</sub> receptors: a complexity of GABA<sub>B</sub>-mediated signaling2018

    • Author(s)
      TERUNUMA Miho
    • Journal Title

      Proceedings of the Japan Academy, Series B

      Volume: 94 Issue: 10 Pages: 390-411

    • DOI

      10.2183/pjab.94.026

    • NAID

      130007529109

    • ISSN
      0386-2208, 1349-2896
    • Year and Date
      2018-12-11
    • Related Report
      2018 Research-status Report
  • [Presentation] Regulatory mechanism of glutamate metabolism in CNS health and disease2021

    • Author(s)
      照沼美穂
    • Organizer
      第64回日本神経化学会大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] アンモニアが脳に与える影響2021

    • Author(s)
      照沼美穂
    • Organizer
      第63回歯科基礎医学会学術大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] The role of extracellular glutamine concentration in regulating astrocytic glutamine synthetase expression2021

    • Author(s)
      那須優介, 照沼美穂
    • Organizer
      第64回日本神経化学会大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] The role of extracellular glutamine concentration in regulating astrocytic glutamine synthetase expression2021

    • Author(s)
      Yusuke Nasu, Koichi Tabeta, Miho Terunuma
    • Organizer
      Society for Neuroscience
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] アストロサイトを介したアルツハイマー病態増悪機構2020

    • Author(s)
      照沼美穂
    • Organizer
      第63回日本神経化学会大会
    • Related Report
      2020 Research-status Report
  • [Presentation] Formation and detoxification of ammonia in the human body2020

    • Author(s)
      Miho Terunuma
    • Organizer
      International Collaborative Symposium on Development of Human Resources in Practical Oral Health and Treatment
    • Related Report
      2020 Research-status Report
  • [Presentation] アンモニアはアストロサイトにおいてアミロイドβの産生を誘導する2020

    • Author(s)
      小松彩夏,岸川咲吏,飯田和泉,照沼美穂
    • Organizer
      新潟歯学会例会
    • Related Report
      2020 Research-status Report
  • [Presentation] カイニン酸型グルタミン酸受容体サブユニットGluK2及びGluK5サブユニット欠損マウスの行動解析2020

    • Author(s)
      飯田和泉,阿部学,崎村建司,照沼美穂
    • Organizer
      第50回日本神経精神薬理学会年会・NPBPPP合同年会
    • Related Report
      2020 Research-status Report
  • [Presentation] アンモニアとアルツハイマー病発症の相関の検討2020

    • Author(s)
      小松彩夏,飯田和泉,原田史子,岸川咲吏,照沼美穂
    • Organizer
      第71回日本薬理学会北部会
    • Related Report
      2020 Research-status Report
  • [Presentation] Ammonia promotes amyloid beta42 production in astrocytes2020

    • Author(s)
      Ayaka Komatsu, Izumi Iida, Sari Kishikawa, Genki Ito, Yusuke Nasu, Miho Terunuma
    • Organizer
      第63回日本神経化学会大会
    • Related Report
      2020 Research-status Report
  • [Presentation] Expression of astrocytic glutamine synthetase is regulated by YAP2020

    • Author(s)
      Sari Kishikawa, Miho Terunuma
    • Organizer
      第63回日本神経化学会大会
    • Related Report
      2020 Research-status Report
  • [Presentation] GluK3-containing Kainate receptors influence the anxiolytic-like activities2020

    • Author(s)
      Miho Terunuma, Izumi Iida, Masahiko Watanabe, Kenji Sakimura
    • Organizer
      第10回武田科学振興財団 薬科学シンポジウム
    • Related Report
      2020 Research-status Report
  • [Presentation] Formation and detoxification of ammonia in the human body.2020

    • Author(s)
      Miho Terunuma
    • Organizer
      International Collaborative Symposium on Development of Human Resources in Practical Oral Health and Treatment.
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] アンモニアによる新規アルツハイマー病関連因子蓄積のメカニズム2019

    • Author(s)
      小松彩夏,岸川咲吏,飯田和泉,照沼美穂
    • Organizer
      第60回新潟生化学会
    • Related Report
      2019 Research-status Report
  • [Presentation] アストロサイトに発現するグルタミン合成酵素の発現調節機構2019

    • Author(s)
      岸川咲吏, 照沼美穂
    • Organizer
      第60回新潟生化学会
    • Related Report
      2019 Research-status Report
  • [Presentation] Ammonia increases the expression of amyloid precursor protein in astrocytes.2019

    • Author(s)
      Ayaka Komatsu, Sari Kishikawa, Izumi Iida, Fumiko Harada and Miho Terunuma
    • Organizer
      NEURO2019(第42回日本神経科学大会/第62回日本神経化学会大会)
    • Related Report
      2019 Research-status Report
  • [Presentation] Ammonia-induced regulation of glutamine synthetase stability in astrocytes.2019

    • Author(s)
      Sari Kishikawa, Miho Terunuma
    • Organizer
      NEURO2019(第42回日本神経科学大会/第62回日本神経化学会大会)
    • Related Report
      2019 Research-status Report
  • [Presentation] Ammonia induces Alzheimer’s disease pathology in astrocytes.2019

    • Author(s)
      Ayaka Komatsu, Sari Kishikawa, Miho Terunuma
    • Organizer
      ISN-ASN
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Ammonia-mediated induction of Alzheimer's disease pathology in astrocytes.2019

    • Author(s)
      Ayaka Komatsu, Sari Kishikawa, Genki Ito, Izumi Iida and Miho Terunuma
    • Organizer
      Neuroscience 2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] 脳の健康と食生活2018

    • Author(s)
      照沼美穂
    • Organizer
      歯科基礎医学会
    • Related Report
      2018 Research-status Report
  • [Presentation] アストロサイトのアンモニア代謝調節機構の解明2018

    • Author(s)
      岸川咲吏,照沼美穂
    • Organizer
      新潟生化学懇話会
    • Related Report
      2018 Research-status Report
  • [Presentation] Ammonium-induced GS degradation undergo proteasome independent pathways2018

    • Author(s)
      Sari Kishikawa, Miho Terunuma
    • Organizer
      WCP2018(国際学会)
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] The effect of hyperglycemia on brain cells.2018

    • Author(s)
      Ayaka Komatsu,Miho Terunuma
    • Organizer
      International Niigata-Taiwan Universities Collaborative Dental Research Symposium
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Remarks] 新潟大学大学院医歯学総合研究科口腔生化学分野ホームページ

    • URL

      https://oral-biochemistry.net/contents/news/index.html#10

    • Related Report
      2021 Annual Research Report
  • [Remarks] 新潟大学歯学部ホームページ

    • URL

      https://www.dent.niigata-u.ac.jp/news/7116/

    • Related Report
      2021 Annual Research Report
  • [Remarks] 新潟大学ホームページ

    • URL

      https://www.niigata-u.ac.jp/news/2022/137933/

    • Related Report
      2021 Annual Research Report

URL: 

Published: 2018-10-12   Modified: 2023-01-30  

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