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Possible involvement of impaired intrinsic microglial clock in Periodontotis-associated exacerbation of Alzheimer's disease

Research Project

Project/Area Number 18K19650
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 57:Oral science and related fields
Research InstitutionYasuda Women's University

Principal Investigator

Nakanishi Hiroshi  安田女子大学, 薬学部, 教授 (20155774)

Co-Investigator(Kenkyū-buntansha) 倪 軍軍  九州大学, 歯学研究院, 助教 (00783953)
Project Period (FY) 2018-06-29 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2018: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Keywordsミクログリア / 時計遺伝子 / 炎症性反応 / アルツハイマー病 / ジンジバリス菌 / 網羅的遺伝子解析 / 時計遺伝 / 脳炎症
Outline of Final Research Achievements

It is well known that disturbances in clock genes affect almost all patients with Alzheimer’s disease (AD). As microglia-mediated neuroinflammation proved to be a driver of AD rather than a result of the disease, we evaluated the relationship between clock gene disturbance and neuroinflammation in microglia and their contribution to the onset of AD. Pro-inflammatory genes in microglia isolated from APP knock-in mice were significantly higher than those isolated from wild-type mice. The expression of pro-inflammatory genes was positively associated with NF-κB activation and negatively associated with the BMAL1 expression. SR9009 induced the activation of microglia, the increased expression of pro-inflammatory genes, and cognitive decline in APP knock-in mice. Therefore, clock gene disturbance in microglia is involved in the early onset of AD through the induction of chronic neuroinflammation.

Academic Significance and Societal Importance of the Research Achievements

ミクログリアの活性化反応を活動期に規制するゲート機構が存在し、ミクログリア分子時計の制御下にあることが想定された。本研究ではREV-ERBalphaの発現量がミクログリアの活性化反応を規制するゲート機構の実体であることを突き止めた。さらに、REV-ERBalphaによるミクログリアにおける炎症反応は、Abetaオリゴマーにより促進されることが明らかとなった。本研究成果より、ミクログリアの時計遺伝子(特にREV-ERBalpha)を制御することによりアルツハイマー病に伴う過剰な慢性炎症を抑制できる可能性が示唆される。

Report

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

    (36 results)

All 2021 2020 2019 2018 2017

All Journal Article (20 results) (of which Int'l Joint Research: 7 results,  Peer Reviewed: 20 results,  Open Access: 18 results) Presentation (14 results) (of which Int'l Joint Research: 1 results,  Invited: 2 results) Book (2 results)

  • [Journal Article] Microglial circadian clock regulation of microglial structural complexity, dendritic spine density and inflammatory response2021

    • Author(s)
      Nakanishi Hiroshi、Ni Junjun、Nonaka Saori、Hayashi Yoshinori
    • Journal Title

      Neurochemistry International

      Volume: 142 Pages: 104905-104905

    • DOI

      10.1016/j.neuint.2020.104905

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Generation of CSF1-Independent Ramified Microglia-Like Cells from Leptomeninges In Vitro2020

    • Author(s)
      Tanaka J, Takahashi H, Yano H, Nakanishi H.
    • Journal Title

      Cells

      Volume: 10 Issue: 1 Pages: 24-37

    • DOI

      10.3390/cells10010024

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Secreted gingipains from Porphyromonas gingivalis induce microglial migration through endosomal signaling by protease-activated receptor 2.2020

    • Author(s)
      Nonaka S, Nakanishi H.
    • Journal Title

      Neurochem. Int.

      Volume: 140 Pages: 104840-104840

    • DOI

      10.1016/j.neuint.2020.104840

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Neural stem cell?specific ITPA deficiency causes neural depolarization and epilepsy2020

    • Author(s)
      Koga Yuichiro、Tsuchimoto Daisuke、Hayashi Yoshinori、Abolhassani Nona、Yoneshima Yasuto、Sakumi Kunihiko、Nakanishi Hiroshi、Toyokuni Shinya、Nakabeppu Yusaku
    • Journal Title

      JCI Insight

      Volume: 5 Issue: 22

    • DOI

      10.1172/jci.insight.140229

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cathepsin regulation on microglial function.2020

    • Author(s)
      Nakanishi H.
    • Journal Title

      Biophys Biochim Acta Proteins Proteom.

      Volume: 1868 Issue: 9 Pages: 140465-140465

    • DOI

      10.1016/j.bbapap.2020.140465

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Microglial cathepsin B as a key driver of inflammatory brain diseases and brain aging.2020

    • Author(s)
      Nakanishi H.
    • Journal Title

      Neural Regener Res

      Volume: 15 Issue: 1 Pages: 25-29

    • DOI

      10.4103/1673-5374.264444

    • Related Report
      2020 Annual Research Report 2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] . Involvement of cathepsins in innate and adaptive immune responses in periodontitis.2020

    • Author(s)
      Yan X, Wu Z, Wang B, Yu T, Hu Y, Wang S, Deng C, Zhao B, Nakanishi H, Zhang X.
    • Journal Title

      Evid Based Complement Alternat Med.

      Volume: 2020 Issue: 1 Pages: 4517587-4517587

    • DOI

      10.1155/2020/4517587

    • Related Report
      2020 Annual Research Report 2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Microglial cathepsin B and Porphyromonas gingivalis gingipains as potential therapeutic targets for sporadic Alzheimer’s disease.2020

    • Author(s)
      Nakanishi H., Nonaka S., Wu Z.
    • Journal Title

      CNS & Neurol Disod. Drug Targets

      Volume: 19 Issue: 7 Pages: 495-502

    • DOI

      10.2174/1871527319666200708125130

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cathepsin E in neutrophils contributes to the generation of neuropathic pain in experimental autoimmune encephalomyelitis.2019

    • Author(s)
      Harada Y, Zhang J, Imari K, Yamasaki R, Ni J, Wu Z, Yamamoto K, Kira JI, Nakanishi H, Hayashi Y.
    • Journal Title

      Pain

      Volume: 160 Issue: 9 Pages: 2050-2062

    • DOI

      10.1097/j.pain.0000000000001596

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Induction of bone repair in rat calvarial defects using a combination of hydroxyapatite with phosphatidylserine liposomes2019

    • Author(s)
      Hatakeyama J, Anan H, Hatakeyama Y, Matsumoto N, Takayama F, Wu Z, Matsuzaki E, Minakami M, Izumi T, Nakanishi H
    • Journal Title

      Journal of Oral Science

      Volume: 61 Issue: 1 Pages: 111-118

    • DOI

      10.2334/josnusd.17-0488

    • NAID

      130007626633

    • ISSN
      1343-4934, 1880-4926
    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] An impaired intrinsic microglial clock system induces neuroinflammatory alterations in the early stage of amyloid precursor protein knock-in mouse brain.2019

    • Author(s)
      Ni J, Wu Z, Meng J, Saito T, Saido TC, Qing H, Nakanishi H.
    • Journal Title

      J. Neuroinflamm.

      Volume: 16 Issue: 1 Pages: 173-173

    • DOI

      10.1186/s12974-019-1562-9

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Pterostilbene, an active component of the dragon’s blood extract, acts as an antiderpressant in adult rats.2019

    • Author(s)
      Yang L, Ran Y, Quan Z, Wang R, Yang Q, Jia Q, Zhang H, Li Y, Peng Y, Liang J, Wang H, Nakanishi H, Deng Y, Qing H.
    • Journal Title

      Psychopharmacology (Berl)

      Volume: 14 Issue: 4 Pages: 658-665

    • DOI

      10.1007/s00213-018-5138-7

    • Related Report
      2019 Research-status Report 2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Mutations of beta-amyloid precursor protein after the consequence of Alzheimer's disease pathogenesis.2019

    • Author(s)
      Li NM, Liu KF, Qiu YJ, Zhang HH, Nakanishi H, Qing H.
    • Journal Title

      Neural Regen Res.

      Volume: 14 Issue: 4 Pages: 658-665

    • DOI

      10.4103/1673-5374.247469

    • Related Report
      2019 Research-status Report 2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Microglial clearance of focal apoptotic synapses.2019

    • Author(s)
      Nonaka S, Nakanishi H.
    • Journal Title

      Neurosci. Lett.

      Volume: 707 Pages: 134317-134317

    • DOI

      10.1016/j.neulet.2019.134317

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Increased expression and altered subcellular distribution of cathepsin B in microglia induce cognitive impairment through oxidative stress and inflammatory response in mice.2018

    • Author(s)
      Ni J, Wu Z, Stoka V, Meng J, Hayashi Y, Peters C, Qing H, Turk V, Nakanishi H. Increased expression and altered subcellular distribution of cathepsin B in microglia induce cognitive impairment through oxidative stress and inflammatory response in mice
    • Journal Title

      Aging Cell

      Volume: . Issue: 1

    • DOI

      10.1111/acel.12856

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A Novel Autoantibody against Plexin D1 in Patients with Neuropathic Pain.2018

    • Author(s)
      Fujii T, Yamasaki R, Iinuma K, Tsuchimoto D, Hayashi Y, Saitoh BY, Matsushita T, Kido MA, Aishima S, Nakanishi H, Nakabeppu Y, Kira JI.
    • Journal Title

      Annals of Neurology

      Volume: 84 Issue: 2 Pages: 208-224

    • DOI

      10.1002/ana.25279

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Manipulation of hippocampal CA3 firing via luminopsins modulates spatial and episodic short-term memory, especially working memory, but not long-term memory.2018

    • Author(s)
      Song D, Yang Q, Lang Y, Wen Z, Xie Z, Zheng D, Yan T, Deng Y, Nakanishi H, Qing H
    • Journal Title

      Neurobiol Learn Mem

      Volume: 155 Pages: 435-445

    • DOI

      10.1016/j.nlm.2018.09.009

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [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 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Brazilian green propolis prevents cognitive decline into mild cognitive impairment in elderly people living at high altitude.2018

    • Author(s)
      Zhu A, Wu Z, Zhong X, Ni J, Li Y, Meng J, Du C, Zhao X, Nakanishi H, Wu S
    • Journal Title

      J Alzheimers Dis.

      Volume: 63 Issue: 2 Pages: 551-560

    • DOI

      10.3233/jad-170630

    • Related Report
      2018 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
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] アルツハイマー病治療のパラダイムシフト -歯周病とミクログリアの不都合な関係-2020

    • Author(s)
      中西 博
    • Organizer
      第142回日本薬学会中国四国支部例会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] Involvement of endosomal signaling in gingipain-induced migration, inflammation response and phagocytosis in microglia after activation of PAR2、2019

    • Author(s)
      Nonaka S, Iseki A, Amano A, Nakanishi Y, Ni J, Wu Z, Nakanishi H.
    • Organizer
      XIV European meeting on glial cells in health and disease (GLIA 2019)
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] An impaired intrinsic microglial clock system induces neuroinflammatory alterations in the early stage of amyloid precursor protein knock-in mouse brain2019

    • Author(s)
      Junjun Ni、中西 博 、武 洲
    • Organizer
      第72回日本薬理学会西南部会
    • Related Report
      2019 Research-status Report
  • [Presentation] Secreted gingipains from Porphyromonas gingivalis induce microglia migration through endosomal signaling by protease-activated receptor 22019

    • Author(s)
      Nonaka S, Nakanishi H.
    • Organizer
      第24回グリア研究会
    • Related Report
      2019 Research-status Report
  • [Presentation] Cathepsin H deficiency suppresses hypoxic-ischemia-induced hippocampal atrophy in mice through reduced secretion of IFN-beta from microglia2019

    • Author(s)
      Ni J, Wu Z, Nakanishi H,
    • Organizer
      第24回グリア研究会
    • Related Report
      2019 Research-status Report
  • [Presentation] カテプシン群と痛みの治療2019

    • Author(s)
      中西 博
    • Organizer
      第18回痛みの研究会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] 脊髄ミクログリアBKチャネルの神経障害性疼痛における役割2019

    • Author(s)
      佐藤泰司、諸橋 徹、林 良憲、板倉沙也子、川口慎憲、中西 博、メレディス アンドレア、石塚 俊晶
    • Organizer
      第92回日本薬理学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] ITPA欠損によるヒトてんかん性脳症のモデルとしての神経幹細胞特異的Itpaノックアウトマウス2018

    • Author(s)
      土本大介、古賀祐一郎、林 良憲、アボルハッサニ ノナ、米嶋康臣、中西 博、中別府雄
    • Organizer
      第41回日本分子生物学会
    • Related Report
      2018 Research-status Report
  • [Presentation] Involvement of reduced microglial BMAL1 expression in excessive neuroinflammation of APP knock-in (APP-KI) mice.2018

    • Author(s)
      Ni J, Wu Z, Nonaka S, Saido TC, Nakanishi H
    • Organizer
      第23回グリア研究
    • Related Report
      2018 Research-status Report
  • [Presentation] チベット薬Ratanasampilは、低酸素によるミクログリアにおける酸化ストレスならびにNF-kappaB活性化に依存した炎症反応を抑制する2018

    • Author(s)
      孟ジェイ、朱愛琴、Junjuin Ni、林 良憲、中西 博、武 洲
    • Organizer
      第71回日本薬理学会西南部会
    • Related Report
      2018 Research-status Report
  • [Presentation] ミクログリアにおけるカテプシン増大と細胞内の分布変化は、酸化ストレスならびに炎症反応を介して認知障害をもたらす2018

    • Author(s)
      Junjuin Ni、武 洲、林 良憲、中西 博
    • Organizer
      第71回日本薬理学会西南部会
    • Related Report
      2018 Research-status Report
  • [Presentation] ブラジル産グリーンプロポリスはチベット高原に住む高齢者の全身炎症を軽減して認知機能の低下を防ぐ2018

    • Author(s)
      朱 愛琴、Junjun Ni、Jie Meng、中西 博、武 洲
    • Organizer
      第60回歯科基礎医学会学術大会
    • Related Report
      2018 Research-status Report
  • [Presentation] チベット薬Ratanasampilは低酸素によるミクログリアにおける酸化ストレスならびにNF-kappaB活性化に依存した炎症反応を抑制する2018

    • Author(s)
      Jie Meng、Junjun Ni、林 良憲、中西 博、朱 愛琴、武 洲
    • Organizer
      第60回歯科基礎医学会学術大会
    • Related Report
      2018 Research-status Report
  • [Presentation] ミクログリアにおけるカテプシンBの発現増加及び細胞内分布変化はマウスにおける酸化ストレスや炎症反応による認知障害を誘発する2018

    • Author(s)
      Junjun Ni、武 洲、林 良憲、中西 博
    • Organizer
      第60回歯科基礎医学会学術大会
    • Related Report
      2018 Research-status Report
  • [Book] 口腔疾患と時間栄養学、「時間栄養学、;時計遺伝子、体内時計、食生活をつなぐ」2020

    • Author(s)
      中西 博
    • Total Pages
      244
    • Publisher
      化学同人
    • ISBN
      9784759820362
    • Related Report
      2020 Annual Research Report
  • [Book] 脳の半分を占める グリア細胞:歯周病菌とミクログリアの不都合な関係 -アルツハイマー病治療のパラダイムシフト-2019

    • Author(s)
      中西 博、野中さおり
    • Publisher
      実験医学増刊号
    • ISBN
      9784758103824
    • Related Report
      2019 Research-status Report

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Published: 2018-07-25   Modified: 2022-01-27  

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