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Elucidation of Alzheimer's disease exacerbation mechanism of periodontitis centering on microglia-related neuroinflammation

Research Project

Project/Area Number 16K11478
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Functional basic dentistry
Research InstitutionKyushu University

Principal Investigator

Take Hiro  九州大学, 歯学研究院, 准教授 (10420598)

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: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords歯周病 / ミクログリア / アルツハイマー病 / アルツハイマー型認知症
Outline of Final Research Achievements

In this study, we have found that systemically exposure of PgLPS, a component of periodontitis Porphyromonas gingivalis (Pg) induces the Alzheimer-disease (AD) -like phenotypes, including learning and memory decrease, microglia-dependent neuroinflammation and hippocampal intraneuronal amyloid A beta accumulation were induced in the wild-type middle-aged mice. It was revealed that AD-like phenotypes did not induced in middle-aged cathepsin (Cat) B deficient mice after exposure PgLPS, therefore it is considered that CatB is a causative enzyme for PgLPS-induced AD-like pathology. On the other hand, spleen hypertrophy associated with a significant increase in dendritic cells and Th17 cells observed in the spleen of wild-type mice after systemically exposure of PgLPS, however the phenotypes in spleen was not observed in mice deficient in CatS deficient mice, thus indicates that CatS may as a causative enzyme of PgLPS induced systemic inflammatory amplification.

Academic Significance and Societal Importance of the Research Achievements

本研究成果は口腔ケアの認知症予防における重要性を広く発信するに加え、CatBならびにCatSの特異的阻害剤は認知症の発症ならびに進行を阻む可能性が示され、今後の展開が期待される。

Report

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

    (37 results)

All 2018 2017 2016

All Journal Article (15 results) (of which Int'l Joint Research: 14 results,  Peer Reviewed: 14 results,  Open Access: 14 results,  Acknowledgement Compliant: 5 results) Presentation (21 results) (of which Int'l Joint Research: 5 results,  Invited: 6 results) Book (1 results)

  • [Journal Article] Ratanasampil Suppresses the Hypoxia-Related Inflammatory Responses by Inhibiting Oxidative Stress and NF-kB Activation in Microglia2018

    • Author(s)
      Zhu Aiqin、Zhong Xin、Nian Wei、Wu Shizheng、Meng Jie、Ni Junjun、Hayashi Yoshinori、Wu Zhou、Nakanishi Hiroshi
    • Journal Title

      Journal of Alzheimer’s Disease & Parkinsonism

      Volume: 08 Issue: 05 Pages: 451-451

    • DOI

      10.4172/2161-0460.1000451

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The critical role of IL-10 in the antineuroinflammatory and antioxidant effects of Rheum tanguticum on activated microglia.2018

    • Author(s)
      Meng J, Ni J, Wu Z, Jiang M, Zhu A, Qing H, Nakanishi H.
    • Journal Title

      Oxid Med Cell Longev

      Volume: 2018:1083596 Issue: 1 Pages: 1-12

    • DOI

      10.1155/2018/1083596

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 歯周病のアルツハイマー病における関与メカニズム2018

    • Author(s)
      武 洲、中西 博
    • Journal Title

      細胞

      Volume: 50 Pages: 45-49

    • Related Report
      2018 Annual Research Report
  • [Journal Article] The Neuroprotective Effects of Brazilian Green Propolis on Neurodegenerative Damage in Human Neuronal SH-SY5Y Cells2017

    • Author(s)
      Ni Junjun、Wu Zhou、Meng Jie、Zhu Aiqin、Zhong Xin、Wu Shizheng、Nakanishi Hiroshi
    • Journal Title

      Oxidative Medicine and Cellular Longevity

      Volume: 2017 Issue: 1 Pages: 1-13

    • DOI

      10.1155/2017/7984327

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Infection of microglia with Porphyromonas gingivalis promotes cell migration and an inflammatory response through the gingipain-mediated activation of protease-activated receptor-2 in mice2017

    • Author(s)
      Liu Yicong、Wu Zhou、Nakanishi Yurika、Ni Junjun、Hayashi Yoshinori、Takayama Fumiko、Zhou Yanmin、Kadawaki Tomoko、Nakanishi Hiroshi
    • Journal Title

      Scientific Reports

      Volume: 7 Issue: 1 Pages: 1-13

    • DOI

      10.1038/s41598-017-12173-1

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Boi-ogi-to (TJ-20), a Kampo Formula, Suppresses the Inflammatory Bone Destruction and the Expression of Cytokines in the Synovia of Ankle Joints of Adjuvant Arthritic Rats2017

    • Author(s)
      Zhang Xinwen、Wu Zhou、Liu Yicong、Ni Junjun、Deng Chunfu、Zhao Baohong、Nakanishi Hiroshi、He Jing、Yan Xu
    • Journal Title

      Evidence-Based Complementary and Alternative Medicine

      Volume: 2017 Issue: 1 Pages: 1-10

    • DOI

      10.1155/2017/3679295

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cathepsin S Is Involved in Th17 Differentiation Through the Upregulation of IL-6 by Activating PAR-2 after Systemic Exposure to Lipopolysaccharide from Porphyromonas gingivalis2017

    • Author(s)
      Dekita Masato、Wu Zhou、Ni Junjun、Zhang Xinwen、Liu Yicong、Yan Xu、Nakanishi Hiroshi、Takahashi Ichiro
    • Journal Title

      Frontiers in Pharmacology

      Volume: 8 Pages: 1-13

    • DOI

      10.3389/fphar.2017.00470

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Dysfunction in diurnal synaptic responses and social behavior abnormalities in cathepsin S-deficient mice2017

    • Author(s)
      Takayama Fumiko、Zhang Xinwen、Hayashi Yoshinori、Wu Zhou、Nakanishi Hiroshi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 490 Issue: 2 Pages: 447-452

    • DOI

      10.1016/j.bbrc.2017.06.061

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cathepsin B plays a critical role in inducing Alzheimer’s disease-like phenotypes following chronic systemic exposure to lipopolysaccharide from Porphyromonas gingivalis in mice2017

    • Author(s)
      Wu Zhou、Ni Junjun、Liu Yicong、Teeling Jessica L.、Takayama Fumiko、Collcutt Alex、Ibbett Paul、Nakanishi Hiroshi
    • Journal Title

      Brain, Behavior, and Immunity

      Volume: 65 Pages: 350-361

    • DOI

      10.1016/j.bbi.2017.06.002

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Overexpression of cathepsin E interferes with neuronal differentiation of P19 embryonal teratocarcinoma cells by degradation of N-cadherin.2017

    • Author(s)
      Harada Y, Takayama F, Tanabe K, Ni J, Hayashu Y, Yamamoto K, Wu Z, Nakanishi H
    • Journal Title

      10.1007/s10571-016-0376-x.

      Volume: 37 Issue: 3 Pages: 437-443

    • DOI

      10.1007/s10571-016-0376-x

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] An EP2 agonist facilitates NMDA-induced outward currents and inhibits dendritic beading through activation of BK channels in mouse cortical neurons.2016

    • Author(s)
      Hayashi Y, Morinaga S, Liu X, Zhang J, Wu Z, Yokoyama T, Nakanishi H
    • Journal Title

      Mediators Inflamm

      Volume: 2016 Pages: 5079597-5079597

    • DOI

      10.1155/2016/5079597

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] BK channels in microglia are required for2016

    • Author(s)
      Yoshinori Hayashi, Saori Morinaga, Jing Zhang, Yasushi Satoh, Andrea Meredith, Takahiro Nakata, Zhou Wu, Shinichi Kohsaka, Kazuhide Inoue, Hiroshi Nakanishi
    • Journal Title

      Nature communications

      Volume: 7 Issue: 1 Pages: 11697-11697

    • DOI

      10.1038/ncomms11697

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Diurnal dynamic behavior of microglia in response to infected bacteria through the UDP-P2Y6 receptor system.2016

    • Author(s)
      Takayama F, Hayashi Y, Wu Z, Liu Y, Nakanishi H.
    • Journal Title

      Sci Rep

      Volume: 6 Issue: 1 Pages: 30006-30006

    • DOI

      10.1038/srep30006

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Cathepsin B regulates collagen expression by fibroblasts via prolonging TLR2/NF-kB activation.2016

    • Author(s)
      Li X, Wu Z, Ni J, Liu Y, Meng J, Yu W, Nakanishi H, Zhou Y
    • Journal Title

      Oxid Med Cell Longev

      Volume: 2016 Issue: 1 Pages: 7894247-7894247

    • DOI

      10.1155/2016/7894247

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Nutrient, microglia aging, and brain aging.2016

    • Author(s)
      Wu Z, Yu J, Zhu A, Nakanishi H
    • Journal Title

      Oxid Med Cell Longev

      Volume: 2016 Issue: 1 Pages: 7498528-7498528

    • DOI

      10.1155/2016/7498528

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Presentation] ジンジバリス菌とアルツハイマー病2018

    • Author(s)
      武 洲
    • Organizer
      第60回歯科基礎医学会学術大会・ メインシンポジウム
    • Related Report
      2018 Annual Research Report
  • [Presentation] 慢性全身性Porphyromonas gingivalis感染に伴う全身性アミロイドβ代謝におけるマクロファージの関与2018

    • Author(s)
      Ran Nie, Junjun Ni, Yoshinori Hayashi, Zhou Wu, Yanmin Zhou
    • Organizer
      第60回歯科基礎医学会学術大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Porphyromonas gingivalis由来LPSの慢性投与は中年モウスにおける骨量低下ならびに記憶低下を誘発する2018

    • Author(s)
      Yebo Gu, Junjun Ni, Zhou Wu, Ichiro Takahashi
    • Organizer
      第60回歯科基礎医学会学術大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Porphyromonas gingivalis 菌慢性末梢感染により老齢femaleマウスミクログリアにおける抗炎症能が低下する2018

    • Author(s)
      中西 悠梨香
    • Organizer
      第60回歯科基礎医学会学術大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Gingipains induce microglial migration through activation of protease-activated receptor-2 (PAR-2)2017

    • Author(s)
      Yicong Liu, Zhou Wu, Hiroshi Nakanishi
    • Organizer
      95tth Annual Meeting of International Association for Dental Research (IADR2017)
    • Place of Presentation
      サンフランシスコ(USA)
    • Year and Date
      2017-03-24
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] 歯周病と認知機能:増悪機序の解明と今後の展望2017

    • Author(s)
      武 洲、中西 博
    • Organizer
      第90回日本薬理学会年会(年会企画シンポジウム:口腔ブレインサイエンスに学ぶ健康長寿)
    • Place of Presentation
      長崎新聞文化ホール(長崎)
    • Year and Date
      2017-03-17
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] The critical roles of gingipains in cell migration and inflammatory response of microglia through activation of protease-activated receptor-2 (PAR-2)2017

    • Author(s)
      Yicong Liu, Zhou Wu, Tomoko Kadowaki, Hiroshi Nakanishi
    • Organizer
      第90回日本薬理学会年会
    • Place of Presentation
      長崎ブリックホール(長崎)
    • Year and Date
      2017-03-17
    • Related Report
      2016 Research-status Report
  • [Presentation] IL-10 plays a pivotal role in anti-inflammatory effects of Pheum tanguticum in activated microglia2017

    • Author(s)
      Jie Meng, Junjun Ni, Zhou Wu, Aiquin Zhu, Hiroshi Nakanishi,
    • Organizer
      第90回日本薬理学会年会
    • Place of Presentation
      長崎ブリックホール(長崎)
    • Year and Date
      2017-03-17
    • Related Report
      2016 Research-status Report
  • [Presentation] Increased expression and altered subcellular distribution of Cathepsin B in microglia induces cognitive impairment through oxidative stress and inflammatory response during aging2017

    • Author(s)
      Junjun Ni, Zhou Wu and Hiroshi Nakanishi
    • Organizer
      the 22nd Annual Meeting of Japan Glia
    • Related Report
      2017 Research-status Report
  • [Presentation] Porphyromonas gingivalis promotes cell migration and an inflammatory response through the gingipain-mediated activation of protease-activated receptor-22017

    • Author(s)
      Yicong Liu, Zhou Wu and Hiroshi Nakanishi
    • Organizer
      the 22nd Annual Meeting of Japan Glia
    • Related Report
      2017 Research-status Report
  • [Presentation] 歯周病菌によるアルツハイマー様脳病態の発症と原因酵素としてのカテプシン群の役割2017

    • Author(s)
      武 洲
    • Organizer
      第58回歯科基礎医学会学術大会・学術シンポジウム
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] Critical roles of cathepsin B in Alzheimer’s disease-like phenotypes following chronic systemic exposure to Porphyromonas gingivalis.2017

    • Author(s)
      Zhou Wu Junjun Ni, Yicong Liu and Hiroshi Nakanishi
    • Organizer
      ISN-ESN Meeting 2017
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Microglia-mediated neuroinflammation in cognitive decline: Evidence, Mechemism and Prevention by natural production.2017

    • Author(s)
      Zhou Wu
    • Organizer
      NEUROTALK-2017
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Gingipain Induce Microglia Migration through activation of protease-activated receptor-22017

    • Author(s)
      Yicong Liu , Zhou Wu and Hiroshi Nakanishi
    • Organizer
      95th Annuak Meeting of International Association for Dental Research (IADR 2017)
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] ミクログリアによる脳炎症を主軸とする歯周病のアルツハイマー病増悪メカニズムの解明2017

    • Author(s)
      武 洲
    • Organizer
      第90回日本薬理学会年会・年会企画シンポジウム
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] ossible involvement of cathepsin H in the negative regulatio2016

    • Author(s)
      Ryo Okada, Yuka Harada, Zhou Wu, Ryo Yamasaki, Hiroshi Nakanishi,
    • Organizer
      第21回グリア研究会
    • Place of Presentation
      千里ライフサイエンスセンター(大阪)
    • Year and Date
      2016-12-03
    • Related Report
      2016 Research-status Report
  • [Presentation] Microglia fascilitate brain aging and cognitive imairment through cathepsin B-dependent oxidative and inflammatory responses2016

    • Author(s)
      Junjun Ni, Zhou Wu, Hiroshi Nakanishi
    • Organizer
      第21回グリア研究会
    • Place of Presentation
      千里ライフサイエンスセンター(大阪)
    • Year and Date
      2016-12-03
    • Related Report
      2016 Research-status Report
  • [Presentation] ミクログリアにおけるIL-10産生分泌を介したRheum tanguticumの抗炎症作用2016

    • Author(s)
      孟ジェイ、武 洲、朱 愛琴、中西 博
    • Organizer
      第69回日本薬理学会西南部会
    • Place of Presentation
      松山大学(愛媛)
    • Year and Date
      2016-11-26
    • Related Report
      2016 Research-status Report
  • [Presentation] Arg-ならびにLys-gingipainによるprotease-activated receptor-2(PAR-2)の活性化を介したミクログリアの細胞遊走誘導2016

    • Author(s)
      劉 訳聡、武 洲、門脇知子、中西 博
    • Organizer
      第69回日本薬理学会西南部会
    • Place of Presentation
      松山大学(愛媛)
    • Year and Date
      2016-11-26
    • Related Report
      2016 Research-status Report
  • [Presentation] Cathepsin B, a novel therapeutic target for microglia-aging2016

    • Author(s)
      Zhou Wu
    • Organizer
      XVth Symposium on Proteases, Inhibitors and Biological Control
    • Place of Presentation
      ポートローズ、スロベニア
    • Year and Date
      2016-09-20
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] 歯周病菌感染による脳内アルツハイマー様病態の誘発メカニズム2016

    • Author(s)
      武 洲、中西 博
    • Organizer
      第58回歯科基礎医学会学術大会(サテライトシンポジウム:健康長寿社会を目指す口腔ブレインサイエンスの最前線)
    • Place of Presentation
      札幌コンベンションセンター(札幌)
    • Year and Date
      2016-08-24
    • Related Report
      2016 Research-status Report
    • Invited
  • [Book] アリツハイマ―病-発症メカニズムと新規診断法・創薬・治療開発2018

    • Author(s)
      武 洲
    • Total Pages
      460
    • Publisher
      エヌ・ティ-エス株式会社、東京、日本
    • Related Report
      2018 Annual Research Report

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Published: 2016-04-21   Modified: 2020-03-30  

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