Analysis of Porphyromonas gingivalis-induced neuroinflammation by multi-photon imaging of microglia dynamics

• Project/Area Number: 15K15684
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Functional basic dentistry
• Research Institution: Kyushu University
• Principal Investigator: Nakanishi Hiroshi 九州大学, 歯学研究院, 教授 (20155774)
• Research Collaborator: TAKAYAMA Fumiko
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: ジンジバリス菌 / ミクログリア / 生体蛍光イメージング / 突起伸展 / P2Y6受容体 / 生体イメージング

Outline of Final Research Achievements

In the present study, we have first shown that cortical microglia extend their processes towards focally injected Porphyromonas gingivalis (P. gingivalis). The focally injected P. gingivalis-induced microglial process extension was significantly increased during the light (sleeping) phase than the dark (waking) phase. In contrast, focally injected ATP-induced microglial process extension was significantly increased during the dark phase than the light phase. Furthermore, in contrast to P2Y12 receptor-mediated mechanism of ATP-induced microglial process extension, P. gingivalis-mediated microglial process extension was mediated by P2Y6 receptors. Therefore, P. gingivalis infiltrated in the brain parenchyma may induce the secretion of UDP from microglia at the site of infiltration, UDP, in turn, induces the process extension of neighboring microglia.

Research Products

• [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: Cell Mol Neurobiol Volume: 37 Pages: 437-443
  • Peer Reviewed / 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
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] BK channels in microglia are required for (2016)
  • 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
  • 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
  • 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
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Cathepsin D deficiency induces oxidative damage in brain pericytes and impairs the blood-brain barrier (2015)
  • Author(s): Yoshinori Hayashi Y, Yuka Koga, Xinwen Zhang, Christoph Peters, Yanagawa Y, Zhou Wu, Takeshi Yokoyama, Hiroshi Nakanishi
  • Journal Title: Molecular and Cellular Neuroscience Volume: 64 Pages: 51-60
  • DOI: 10.1016/j.mcn.2014.12.002
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The Critical Role of Proteolytic Relay through Cathepsins B and E in the Phenotypic Change of Microglia/Macrophage (2015)
  • Author(s): XJunjun Ni, Zhou Wu, Christoph Peterts, Kenji Yamamoto, Hong Qing, and Hiroshi Nakanishi2015
  • Journal Title: Journal of Neuroscience Volume: 35 Issue: 36 Pages: 12488-12501
  • DOI: 10.1523/jneurosci.1599-15.2015
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The downwardspiralofperiodontitisanddiabetesinAlzheimer's disease: Extendinghealthylifeexpectancythroughoralhealth (2015)
  • Author(s): Hiroshi Nakanishi, Zhou WU
  • Journal Title: Journal of Oral Biosciences Volume: 57 Issue: 3 Pages: 139-142
  • DOI: 10.1016/j.job.2015.05.002
  • Peer Reviewed
• [Journal Article] Lessons from Microglia Aging for the Link between Inflammatory Bone Disorders and Alzheimer’s Disease (2015)
  • Author(s): Zhou Wu, Hiroshi Nakanishi
  • Journal Title: Journal of Immunology Research Volume: 2015 Pages: 471342-471342
  • DOI: 10.1155/2015/471342
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The Neuroprotective Effects of Ratanasampil on Oxidative Stress-Mediated Neuronal Damage in Human Neuronal SH-SY5Y Cells (2015)
  • Author(s): Aiqin Zhu, Zhou Wu, Jie Meng, Patrick L. McGeer, Yi Zhu, Hiroshi Nakanishi, and Shizheng Wu
  • Journal Title: Oxidative Medicine and Cellular Longevity Volume: 2015 Pages: 1-10
  • DOI: 10.1155/2015/792342
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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
  • 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
  • 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
• [Presentation] IL-10 plays a pivotal role in anti-inflammatory effects of Pheum tanguticum in activated microglia (2017)
  • 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
• [Presentation] Possible involvement of cathepsin H in the negative regulation of T cell activation in experimental autoimmune encepalomyelitis (EAE) (2016)
  • 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
• [Presentation] Microglia fascilitate brain aging and cognitive imairment through cathepsin B-dependent oxidative and inflammatory responses, (2016)
  • 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
• [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、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
• [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、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
• [Presentation] Pathological roles of microglial cathepsins in chronic pain (2016)
  • Author(s): Hiroshi Nakanishi
  • 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: 2016-09-30
  • 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
  • Invited
• [Presentation] ATPならびにPorphyromonas gingivalis（PG）局所注入により惹起されるミクログリア突起の集積とその日内変化に関する生体イメージング解析 (2015)
  • Author(s): 髙山扶美子、林 良憲、武 洲、中西
  • Organizer: 第57回歯科基礎医学会学術大会
  • Place of Presentation: 朱鷺メッセ新潟
  • Year and Date: 2015-09-11
• [Presentation] Periodontitis and Alzheimer’s disease (AD) (1): A possible role of leptomeninges in transduction of inflammatory signals from peripheral macrophages to microglia in the response to lipopolyssacharide from Porphyromonas gingivalis (2015)
  • Author(s): Yicong Liu、Zhou Wu、 Hiroshi Nakanishi
  • Organizer: 第57回歯科基礎医学会学術大会
  • Place of Presentation: 朱鷺メッセ新潟
  • Year and Date: 2015-09-11
• [Presentation] Periodontitis and Alzheimer’s disease (AD) (2): Critical roles of cathepsin B in AD-like phenotypes in middle-aged mice following chronic systemic treatment with lipopolyssacharide from Porphyromonas gingivalis (2015)
  • Author(s): Junjun Ni、Zhou Wu、 Hiroshi Nakanishi
  • Organizer: 第57回歯科基礎医学会学術大会
  • Place of Presentation: 朱鷺メッセ新潟
  • Year and Date: 2015-09-11
• [Presentation] Lessons from cathepsin deficient mice on human brain diseases (2015)
  • Author(s): Hiroshi Nakanishi
  • Organizer: The 4th International Conference and Exhibition on Neurology & Therapeutics
  • Place of Presentation: Holiday Inn Rome Aurelia
  • Year and Date: 2015-07-25
  • Int'l Joint Research / Invited
• [Presentation] Modulator actions of microglial cathepsins in brain diseases (2015)
  • Author(s): Hiroshi Nakanishi
  • Organizer: Cold Spring Harbor Asia（CSHA Conference 2015）: New Insights into Glia Function & Dysfunction
  • Place of Presentation: Worldhotel Grand Dushulake Suzhou
  • Year and Date: 2015-06-22
  • Int'l Joint Research / Invited