Development of early clinical reagents for Alzheimer's disease using citrullinated proteins as index

• Project/Area Number: 15K15104
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Human pathology
• Research Institution: Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology
• Principal Investigator: Ishigami Akihito 地方独立行政法人東京都健康長寿医療センター(東京都健康長寿医療センター研究所), 東京都健康長寿医療センター研究所, 研究部長 (50270658)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 神経変性疾患 / 脳神経疾患

Outline of Final Research Achievements

We have identified for the first time citrullinated Alzheimer's disease-related proteins in the brains of Alzheimer's disease patients. We also succeeded in developing clinical laboratory diagnostic reagents that quantify it’s citrullinated proteins. It has potential to be useful as a clinical diagnostic agent for quantifying citrullinated Alzheimer's disease-related proteins. In the future, we will verify the usefulness as an early clinical diagnostic agent for Alzheimer's disease.

Academic Significance and Societal Importance of the Research Achievements

アルツハイマー病の早期臨床検査試薬は未だ開発されていない。本研究成果は、アルツハイマー病を診断する臨床診断薬に繋がる可能性がある。

Research Products

• [Journal Article] Accumulation of citrullinated glial fibrillary acidic protein in a mouse model of bile duct ligation-induced hepatic fibrosis (2018)
  • Author(s): Kim Sung-Eun、Park Ji Won、Kim Mo-Jong、Jang Byungki、Jeon Yong-Chul、Kim Hee-Jun、Ishigami Akihito、Kim Hyoung Su、Suk Ki Tae、Kim Dong Joon、Park Choong Kee、Choi Eun-Kyoung、Jang Myoung-Kuk
  • Journal Title: PLOS ONE Volume: 13 Issue: 8 Pages: e0201744-e0201744
  • DOI: 10.1371/journal.pone.0201744
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Induction of peptidylarginine deiminase 2 and 3 by dibutyryl cAMP via cAMP-PKA signaling in human astrocytoma U-251MG cells (2017)
  • Author(s): Masutomi Hirofumi、Kawashima Saki、Kondo Yoshitaka、Uchida Yoshiaki、Jang Byungki、Choi Eun-Kyoung、Kim Yong-Sun、Shimokado Kentaro、Ishigami Akihito
  • Journal Title: Journal of Neuroscience Research Volume: 95 Issue: 7 Pages: 1503-1512
  • DOI: 10.1002/jnr.23959
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Anti-cyclic citrullinated glucose-6-phosphate isomerase peptide-7 (CCG-7) antibodies were suppressed by biologics treatment and deposited to citrullinated proteins in CD68-positive cells in the RA synovium (2017)
  • Author(s): Umeda Naoto、Matsumoto Isao、Tanaka Yuki、Kawaguchi Hoshimi、Ebe Hiroshi、Kagami Yayoi、Ishigami Akihito、Sumida Takayuki
  • Journal Title: Modern Rheumatology Volume: 27 Issue: 5 Pages: 914-916
  • DOI: 10.1080/14397595.2016.1270388
  • Peer Reviewed
• [Journal Article] Carbamylated albumin is one of the target antigens of anti-carbamylated protein antibodies. (2017)
  • Author(s): Nakabo S, Hashimoto M, Ito S, Furu M, Ito H, Fujii T, Yoshifuji H, Imura Y, Nakashima R, Murakami K, Kuramoto N, Tanaka M, Satoh J, Ishigami A, Morita S, Mimori T, Ohmura K.
  • Journal Title: Rheumatology (Oxford) Volume: in press Issue: 7 Pages: 1217-1226
  • DOI: 10.1093/rheumatology/kex088
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The Peptidylarginine Deiminase Inhibitor Cl-Amidine Suppresses Inducible Nitric Oxide Synthase Expression in Dendritic Cells (2017)
  • Author(s): Jang Byungki、Ishigami Akihito、Kim Yong-Sun、Choi Eun-Kyoung
  • Journal Title: International Journal of Molecular Sciences Volume: 18 Issue: 11 Pages: 2258-2258
  • DOI: 10.3390/ijms18112258
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hypoxia-induced production of peptidylarginine deiminases and citrullinated proteins in malignant glioma cells. (2016)
  • Author(s): Sase T, Arito M, Onodera H, Omoteyama K, Kurokawa MS, Kagami Y, Ishigami A, Tanaka Y, Kato T.
  • Journal Title: Biochem Biophys Res Commun. Volume: 482 Issue: 1 Pages: 50-56
  • DOI: 10.1016/j.bbrc.2016.10.154
  • Peer Reviewed
• [Journal Article] Prevalence of soluble peptidylarginine deiminase 4 (PAD4) and anti-PAD4 antibodies in autoimmune diseases. (2016)
  • Author(s): Umeda N, Matsumoto I, Kawaguchi H, Kurashima Y, Kondo Y, Tsuboi H, Ogishima H, Suzuki T, Kagami Y, Sakyu T, Ishigami A, Maruyama N, Sumida T.
  • Journal Title: Clin Rheumatol. Volume: 35 Issue: 5 Pages: 1181-1188
  • DOI: 10.1007/s10067-015-3082-z
  • Peer Reviewed
• [Journal Article] Citrullination of glial intermediate filaments is an early response in retinal injury. (2016)
  • Author(s): Wizeman JW, Nicholas AP, Ishigami A, Mohan R.
  • Journal Title: Mol Vis. Volume: 22 Pages: 1137-1155
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mass spectrometric identification of citrullination sites and immunohistochemical detection of citrullinated glial fibrillary acidic protein in Alzheimer's disease brains. (2015)
  • Author(s): Ishigami, A., Masutomi, H., Handa, S., Nakamura, M., Nakaya, S., Uchida, Y., Saito, Y., Murayama, S., Jang, B., Jeon, Y.C., Choi, E.K., Kim, Y.S., Kasahara, Y., Maruyama, N., Toda, T.
  • Journal Title: J. Neurosci. Res. Volume: 93 Issue: 11 Pages: 1664-1674
  • DOI: 10.1002/jnr.23620
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Age-associated decrease of senescence marker protein-30/gluconolactonase in individual mouse liver cells: Immunohistochemistry and immunofluorescence. (2015)
  • Author(s): Ishigami, A., Masutomi, H., Handa, S., Maruyama, N.
  • Journal Title: Geriatr. Gerontol. Int. Volume: 15 Issue: 6 Pages: 804-810
  • DOI: 10.1111/ggi.12347
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] アルツハイマー病とシトルリン化蛋白質 (2015)
  • Author(s): 石神昭人
  • Journal Title: 医学のあゆみ Volume: 255 Pages: 889-893
  • Peer Reviewed
• [Presentation] アルツハイマー病診断薬の開発 (2017)
  • Author(s): 近藤嘉高、石神昭人
  • Organizer: TOBIRA第6回研究交流フォーラム
• [Presentation] Peptidylarginine deiminase 2 (PAD2) in mouse skeletal muscle. (2017)
  • Author(s): 成田昂平、近藤嘉高、野田義博、町田修一、吉田雅幸、石神昭人
  • Organizer: 日本基礎老化学会第40回大会
• [Presentation] 新規に開発した抗化学修飾シトルリン化モノクローナル抗体を用いた脳におけるシトルリン化タンパク質の検出 (2016)
  • Author(s): 近藤嘉高、成田昂平、石神昭人
  • Organizer: 第39回 日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜, 横浜市, 神奈川県
  • Year and Date: 2016-11-30
• [Presentation] マウス骨格筋におけるペプチジルアルギニンデイミナーゼ2（PAD2)の生化学的解析 (2016)
  • Author(s): 成田昂平、近藤嘉高、増冨裕文、吉田雅幸、石神昭人
  • Organizer: 第39回 日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜, 横浜市, 神奈川県
  • Year and Date: 2016-11-30
• [Presentation] Dibutyryl-cAMP induced PAD expressions via PKA pathway in human astrocytoma U-251MG cells. (2016)
  • Author(s): Masutomi, H., Kawashima, S., Shimokado, K., Ishigami, A.
  • Organizer: 第39回日本神経科学大会
  • Place of Presentation: パシフィコ横浜, 横浜市, 神奈川県
  • Year and Date: 2016-07-20
• [Presentation] Citrullinated glial fibrillary acidic protein in Alzheimer’s diseased brains. (2016)
  • Author(s): Ishigami, A.
  • Organizer: 2016 Spring International Conference of the Korean Society for Gerontology and the 15th Korea-Japan Gerontologist Joint Meeting
  • Place of Presentation: Hotel Laonzena, Convention Hall, Daegu, Korea
  • Year and Date: 2016-06-15
  • Int'l Joint Research / Invited
• [Presentation] Abnormal protein citrullination in Alzheimer’s disease. (2016)
  • Author(s): Ishigami, A.
  • Organizer: 11th Asia-Pacific Microscopy Conference (APMC11)
  • Place of Presentation: Phuket Graceland Resort and Spa, Phuket, Thailand
  • Year and Date: 2016-05-23
  • Int'l Joint Research / Invited
• [Presentation] シトルリン化タンパク質を検出する臨床検査試薬の開発 (2016)
  • Author(s): 天野晶子、近藤嘉高、石神昭人
  • Organizer: TOBIRA第5回研究交流フォーラム
  • Place of Presentation: ソラシティカンファレンスセンター内ソラシティホール, 文京区, 東京都
• [Presentation] Abnormal protein citrullination in Alzheimer’s disease. (2015)
  • Author(s): Ishigami, A.
  • Organizer: The 10th IAGG Asia/Oceania Regional Congress (IAGG 2015)
  • Place of Presentation: The International Convention and Exhibition Centre, Chiang Mai, Thailand
  • Year and Date: 2015-10-19
  • Int'l Joint Research / Invited
• [Presentation] Detection of citrullinated proteins in the postmortem brain from wild-type and PAD2-knockout mice using newly developed anti-modified citrulline monoclonal antibodies. (2015)
  • Author(s): Kagami, Y. Masutomi, H., Choi, E.K., Kim, Y.S., Maruyama, N., Ishigami, A.
  • Organizer: The 10th IAGG Asia/Oceania Regional Congress (IAGG 2015)
  • Place of Presentation: The International Convention and Exhibition Centre, Chiang Mai, Thailand
  • Year and Date: 2015-10-19
  • Int'l Joint Research
• [Presentation] Abnormal accumulation of citrullinated proteins in Alzheimer’s disease. (2015)
  • Author(s): Ishigami, A.
  • Organizer: The 19th Thai Neuroscience Society Conference 2015
  • Place of Presentation: Mahidol University, Salaya, Nakhonpathom, Thailand
  • Year and Date: 2015-10-16
  • Int'l Joint Research / Invited
• [Presentation] ヒトアストロサイトーマ細胞株U-251MG細胞でのcAMPによるPADs誘導、及びシトルリン化タンパク質の増加. (2015)
  • Author(s): 増冨裕文、下門顕太郎、石神昭人
  • Organizer: 第38回日本基礎老化学会大会
  • Place of Presentation: パシフィコ横浜、横浜、神奈川
  • Year and Date: 2015-06-12
• [Presentation] シトルリン化タンパク質特異的モノクローナル抗体の確立. (2015)
  • Author(s): 加賀美弥生、増冨裕文、丸山直記、石神昭人
  • Organizer: 第38回日本基礎老化学会大会
  • Place of Presentation: パシフィコ横浜、横浜、神奈川
  • Year and Date: 2015-06-12
• [Book] Update on Deimination in Alzheimer’s Disease. In: Protein Deimination in Human Health and Disease. (2017)
  • Author(s): Kondo, Y., Choi, E.K., Kim, Y.S., Ishigami, A.
  • Total Pages: 466
  • Publisher: Springer
• [Remarks] 東京都健康長寿医療センター研究所 老化制御研究チーム 分子老化制御
  • URL: http://www.aging-regulation.jp/
• [Patent(Industrial Property Rights)] アルツハイマー病の診断を補助する方法及びアルツハイマー病の診断薬 (2017)
  • Inventor(s): 石神昭人、近藤嘉高、佐久拓弥、内田好昭
  • Industrial Property Rights Holder: 石神昭人、近藤嘉高、佐久拓弥、内田好昭
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017