脳組織サイトカイン環境の加齢に伴う炎症性変化を誘導する髄膜・脈絡叢の免疫系構築

• Project/Area Number: 12J40278
• Research Category: Grant-in-Aid for JSPS Fellows
• Allocation Type: Single-year Grants
• Section: 国内
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Institute for Developmental Research, Aichi Human Service Center
• Principal Investigator: 石井 さなえ 愛知県心身障害者コロニー発達障害研究所, 病理学部, 特別研究員(RPD)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,960,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,200,000 (Direct Cost: ¥1,200,000); Fiscal Year 2012: ¥1,200,000 (Direct Cost: ¥1,200,000)
• Keywords: サイトカイン / 髄膜 / 脈絡叢 / 老化 / 炎症 / 髄膜・脈絡叢 / 加齢 / LPS / 海馬 / MultiPlex / 髄膜免疫系 / 骨髄内骨髄移植 / インターフェイス

Outline of Annual Research Achievements

本年度は以下の3点の解析を行い、①を論文にまとめた。②③は論文作成中である。
①若齢、老齢のSAMP10マウスと同月齢のB6マウスの間脳における10種類のサイトカインをLuminex MultiPlexアッセイにより一斉定量した。その結果、老齢SAMP10マウスの間脳にはCCL11, CXCL1, CXCL10, G-CSF, IL-6が同月齢のB6マウスに比べて有意に高濃度であり、免疫染色の結果、脈絡叢付着領域のアストロサイト、脳室周囲のアストロサイト及びタニサイトが強発現することがわかった。
②LPS(3mg/kg)を腹腔内投与した1, 4, 24時間後に脾臓と海馬を回収し、Luminex MultiPlexアッセイにより15種類のサイトカインを一斉定量した。その結果、LPS投与後に海馬では10種類のサイトカインが増加した。免疫染色の結果、LPS投与４時間後に増加するサイトカインは、脈絡叢及び髄膜の細胞、血管内皮細胞が発現し、その受容体は脳表や血管周囲のアストロサイトの終足に発現した。LPS投与24時間後に増加するサイトカインはアストロサイトが発現した。
③7日, 4週齢, 2, 8, 13, 20カ月齢のSAMP10マウス、コントロールマウス(SAMR1マウス、B6マウス)を用いて、海馬における10種類のサイトカイン濃度をLuminex MultiPlexアッセイにて定量した。その結果、加齢により増加するのはCXCL10のみで、B6マウスやSAMR1マウスに比べてSAMP10マウスでは早期に増加した。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Increased recruitment of bone marrow-derived cells into the brain associated with altered brain cytokine profile in senescence-accelerated mice (2015)
  • Author(s): Hasegawa-Ishii S., Inaba M., Ming Li., Ming S., Umegaki H., Ikehara S. and Shimada A.
  • Journal Title: Brain Struct. Funct. Volume: in press
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Dynamics of bone marrow-derived cells relevant to the brain-immune cell-cell interactions under non-inflammatory conditions. (2014)
  • Author(s): Hasegawa-Ishii S., Inaba M., Li Ming., Umegaki H., Ikehara S. and Shimada A.
  • Journal Title: Curr. Trends Neurol. Volume: 8 Pages: 39-52
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Novel flame-shift mutation in Slc5a2 encoding SGLT2 in a strain of senescence-accelerated mouse SAMP10. (2014)
  • Author(s): Unno K., Yamamoto H., Toda M., Hagiwara S., Iguchi K., Hoshino M., Takabayashi F., Hasegawa-Ishii S., Shimada A., Hosokawa M., Higuchi K and Mori M.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 454 Issue: 1 Pages: 89-94
  • DOI: 10.1016/j.bbrc.2014.10.039
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] 知的障害および発達障害の病態形成に関与する脳と免疫系の相互作用. (2014)
  • Author(s): 島田厚良、石井さなえ.
  • Journal Title: 中部大学現代教育学部紀要 Volume: 7 Pages: 21-25
  • NAID: 40020371354
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Niemann-Pick disease type Cl predominantly involving the front otemporal region, with cortical and brainstem Lewy bodies : An autopsy case. (2014)
  • Author(s): Chiba Y., Komori H., Takei S., Hasegawa-Ishii S., Kawamura N., Adachi K., Nanba E., Hosokawa M., Enokido Y., Kouchi Z., Yoshida F., Shimada A.
  • Journal Title: Neuropathology : Volume: 34(1) Issue: 1 Pages: 49-57
  • DOI: 10.1111/neup.12047
  • Peer Reviewed
• [Journal Article] Excitotoxicity-induced immediate surge in hippocampal prostanoid production has latent effects that promote chronic progressive neuronal death. (2013)
  • Author(s): Yoshikawa K., Kita Y., Furukawa A., Kawamura N., Hasegawa-Ishii S., Chiba Y., Takei S., Maruyama K., Shimizu T., Shimada A.
  • Journal Title: Prostaglandins Leukot Essent Fatty Acids. Volume: 88(5) Issue: 5 Pages: 373-381
  • DOI: 10.1016/j.plefa.2013.02.007
  • Peer Reviewed
• [Journal Article] Exome sequencing of senescence-accelerated mice (SAM) reveals deleterious mutations in degenerative disease-causing genes. (2013)
  • Author(s): Tanisawa K., Mikami E., Fuku N., Honda Y., Honda S., Ohsawa I., Ito M., Endo S., Ihara K., Ohno K., Kishimoto Y., Ishigami A., Maruyama N., Sawabe M., Iseki H., Okazaki Y., Hasegawa-Ishii S., Takei S., Shimada A., Hosokawa M., Mori M., Higuchi K., Takeda T., Higuchi M., Tanaka M.
  • Journal Title: BMC Genomics. Volume: 14(1): Issue: 1 Pages: 248-248
  • DOI: 10.1186/1471-2164-14-248
  • Peer Reviewed / Open Access
• [Journal Article] Immunohistochemical localization of aggresomal proteins in glial cytoplasmic inclusions in multiple system atrophy. (2012)
  • Author(s): Chiba Y., Takei S., Kawamura N., Kawaguchi Y., Sasaki K., Hasegawa-Ishii S., Furukawa A., Hosokawa M., Shimada A.
  • Journal Title: Neuropathol. Appl. Neurobiol. Volume: 38(6) Issue: 6 Pages: 559-71
  • DOI: 10.1111/j.1365-2990.2011.01229.x
  • Peer Reviewed
• [Journal Article] Immunohistochemical demonstration of increased prostaglandin F(2α) levels in the rat hippocampus following kainic acid-induced seizures. (2012)
  • Author(s): Takei S., Hasegawa-lshii S., Uekawa A., Chiba Y., Umegaki H., Hosokawa M., Woodward DF., Watanabe K., Shimada A.
  • Journal Title: Neuroscience. Volume: 218 Pages: 295-304
  • Peer Reviewed
• [Journal Article] Selective localization of bone marrow-derived ramified cells in the brain adjacent to the attachments of choroid plexus. (2012)
  • Author(s): Hasegawa-Ishii S, Shimada A, Inaba M, Li M, Shi M, Kawamura N, Takei S, Chiba Y, Hosokawa M, Ikehara S.
  • Journal Title: Brain Behav Immun. Volume: 29 Pages: 82-97
  • DOI: 10.1016/j.bbi.2012.12.010
  • Peer Reviewed
• [Journal Article] 脳と免疫系の相互作用という観点から老化促進モデルマウスをとらえる (2012)
  • Author(s): 島田厚良、石井さなえ
  • Journal Title: 基礎老化研究 Volume: 36(1) Pages: 13-20
  • NAID: 10030253433
  • Peer Reviewed
• [Presentation] Brain cytokine change associated with enhanced bone marrow cell recruitment to the brain in SAM mice. (2014)
  • Author(s): HASEGAWA-ISHII, S., IKEHARA, S., INABA, M., LI, M., SHI, M., SHIMADA, A.
  • Organizer: 第37回日本基礎老化学会
  • Place of Presentation: 名古屋
  • Year and Date: 2014-06-26 – 2014-06-27
• [Presentation] Proinflammatory cytokine milieu of the brain precedes age-related neurodegeneration in SAMP10 mice. (2014)
  • Author(s): SHIMADA, A., HASEGAWA-ISHII, S., INABA, M.
  • Organizer: 第37回日本基礎老化学会
  • Place of Presentation: 名古屋
  • Year and Date: 2014-06-26 – 2014-06-27
• [Presentation] 末梢の炎症に応答する脳内サイトカイン受容・産生機構の組織細胞基盤 (2014)
  • Author(s): 石井さなえ、稲葉宗夫、武井史郎、島田厚良
  • Organizer: 第55回日本神経病理学会
  • Place of Presentation: 東京
  • Year and Date: 2014-06-05 – 2014-06-07
• [Presentation] Changes in profiles of brain cytokines associated with enhanced recruitment of bone marrow-derived cells into the brain in senescence-accelerated mice. (2014)
  • Author(s): Hasegawa-Ishii, S., Ikehara, S., Inaba, M., Li, M., Shi, M., Takei, S. and Shimada, A.
  • Organizer: 21st PsychoNeuroImmunology Resarch Society annual meeting
  • Place of Presentation: ペンシルバニア
  • Year and Date: 2014-05-28 – 2014-05-31
• [Presentation] Enhanced recruitment of bone marrow-derived cells into the brain parenchyma in senescence-accelerated mice. (2014)
  • Author(s): Hasegawa-Ishii, S.
  • Organizer: Neural & Behavioral Sciences Seminar Series
  • Place of Presentation: 米ペンシルバニア州立大学
  • Year and Date: 2014-05-27
  • Invited
• [Presentation] Enhanced recruitment of bone marrow-derived cells into the brain parenchyma in senescence-accelerated mice (2013)
  • Author(s): Sanae Hasegawa-Ishii, Atsuyoshi Shimada
  • Organizer: 3rd Asia Association of Aging Research
  • Place of Presentation: International Conference center, University of Seoul(ソウル、韓国)
  • Year and Date: 2013-11-09
  • Invited
• [Presentation] Selective localization of bone marrow-derived ramified cells in the brain adjacent to the attachments of choroid plexus*Trainee Awardを受賞。 (2013)
  • Author(s): Sanae Hasegawa-Ishii, Atsuyoshi Shimada, Muneo Inaba, Ming Li, Ming Shi, Shiro Takei and Susumu Ikehara
  • Organizer: 20^<th> Annual Meeting of The PsychoNeurolm munology Research Society
  • Place of Presentation: Radisson Blu Royal Park Hotel(ストックホルム、スウェーデン)
  • Year and Date: 2013-06-08
• [Presentation] 脳と免疫系の接点としての脈絡叢間質および付着部における細胞動態とサイトカイン発現 (2013)
  • Author(s): 石井さなえ、島田厚良、稲葉宗夫、李銘、石明、河村則子、武井史郎、千葉陽一、細川昌則、池原進
  • Organizer: 第54回日本神経病理学会
  • Place of Presentation: タワーホール船堀(東京)
  • Year and Date: 2013-04-25
• [Presentation] 骨髄由来免疫系細胞が健常脳に進入する新たな経路:骨髄内骨髄移植による組織学的同定。 (2012)
  • Author(s): 石井さなえ、島田厚良、稲葉宗夫、李銘、石明、河村則子、武井史郎、千葉陽一、榎戸靖、河内全、細川昌則、池原進
  • Organizer: 第53回日本神経病理学会
  • Place of Presentation: 朱鷺メッセ(新潟)
  • Year and Date: 2012-06-30
• [Presentation] 老化促進モデルマウスにみられる骨髄由来細胞の脳実質へのリクルートの亢進。 (2012)
  • Author(s): 島田厚良、石井さなえ、稲葉宗夫、李銘、石明、河村則子、武井史郎、千葉陽一、榎戸靖、河内全、細川昌則、池原進
  • Organizer: 第53回日本神経病理学会
  • Place of Presentation: 朱鷺メッセ(新潟)
  • Year and Date: 2012-06-30
• [Presentation] Intra bone marrow procedure facilitates entry of transplanted bone marrow cells through the tenia of choroid plexus into brain parenchyma. (2012)
  • Author(s): Sanae Hasegawa-lshii, Atsuyoshi Shimada, Muneo Inaba, Ming Li, Ming Shi, Noriko Kawamura, Shiro Takei, Susumu Ikehara
  • Organizer: 19^<th> Annual Meeting of The PsychoNeurolmmunology Research Society
  • Place of Presentation: Grand Hyatt Hotel (San Diego)
  • Year and Date: 2012-06-07
• [Presentation] Enhanced recruitment of bone marrow-derived cells into the brain parenchyma in senescence-accelerated mice. (2012)
  • Author(s): Atsuyoshi Shimada, Sanae Hasegawa-Ishii, Muneo Inaba, Ming Li, Ming Shi, Noriko Kawamura, Shiro Takei, Susumu Ikehara
  • Organizer: 19^<th> Annual Meeting of The PsychoNeurolmmunology Research Society
  • Place of Presentation: Grand Hyatt Hotel (San Diego)
  • Year and Date: 2012-06-07
• [Book] The senescence-accelerated mouse (SAM) : Achievements and Future Directions. (Toshio Takeda, ed.) (2013)
  • Author(s): Shimada A., Hasegawa-Ishii S., Furukawa A.
  • Publisher: SAMP10 strain as a model for the study of brain aging(In Press)