The role of NAD in demyelinating disease

• Project/Area Number: 18K06501
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 46020:Anatomy and histopathology of nervous system-related
• Research Institution: Kanazawa University
• Principal Investigator: Hattori Tsuyoshi 金沢大学, 医学系, 准教授 (50457024)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 脱髄 / 神経炎症 / アストロサイト / ミクログリア / 多発性硬化症 / グリア細胞 / 神経障害 / 神経変性疾患 / ニコチンアミド / 脱髄疾患 / NAD / ミエリン

Outline of Final Research Achievements

Deletion of CD38 attenuated Cuprizone-induced neuroinflammation and demyelination by increasing brain NAD+ level. Compounds which increase brain NAD+ level such as apigenin and NR suppressed neuroinflammation. Therefore, NAD+-boosting compounds might be possible therapeutic molecules not only for demyelinating diseases such as Multiple Sclerosis but also for other neuroinflammation-related diseases such as neurodegenerative diseases and depression.

Academic Significance and Societal Importance of the Research Achievements

脳の中の炎症（神経炎症）を起こすメカニズムにおいてグリア細胞に発現するCD38とNAD+という分子が重要であることが明らかとなった。また、NAD+を増加させる化合物を用いることにより神経炎症を制御することが可能であることが明らかとなったため、今後、これらの知見が脱髄疾患のみならず神経変性疾患等の神経炎症関連疾患における治療へとつながる可能性を見出した。

Research Products

• [Int'l Joint Research] City of Hope National Medical Center/University of Iowa(米国)
• [Int'l Joint Research] University of Iowa(米国)
• [Int'l Joint Research] Iowa University(米国)
• [Journal Article] Abnormal social behavior and altered gene expression in mice lacking NDRG2 (2021)
  • Author(s): Takarada-Iemata Mika、Yoshihara Toru、Okitani Nahoko、Iwata Keiko、Hattori Tsuyoshi、Ishii Hiroshi、Roboon Jureepon、Nguyen Dinh Thi、Fan Qiyan、Tamatani Takashi、Nishiuchi Takumi、Asano Masahide、Hori Osamu
  • Journal Title: Neuroscience Letters Volume: 743 Pages: 135563-135563
  • DOI: 10.1016/j.neulet.2020.135563
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Neuroprotective effects of endogenous secretory receptor for advanced glycation end-products in brain ischemia (2020)
  • Author(s): Simizu Y, Harashima A, Munesue S, Oishi M, Hattori T, Hori O, Kitao Y, Yamamoto H, Leerach N, Nakada M, Yamamoto Y, Hayashi Y
  • Journal Title: Aging Dis Volume: 11 Issue: 3 Pages: 547-547
  • DOI: 10.14336/ad.2019.0715
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Deletion of CD38 and supplementation of NAD + attenuate axon degeneration in a mouse facial nerve axotomy model (2020)
  • Author(s): Takaso Y, Noda M, Hattori T, Roboon J, Hatano M, Sugimoto H, Brenner C, Yamamoto Y, Okamoto H, Higashida H, Ito M, Yoshizaki T, Hori O.
  • Journal Title: Sci Rep Volume: 10 Issue: 1 Pages: 17795-17795
  • DOI: 10.1038/s41598-020-73984-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A monoclonal antibody raised against a synthetic oxytocin peptide stains mouse hypothalamic neurones (2020)
  • Author(s): Kogami Yuji、Tsuji Takahiro、Tsuji Chiharu、Yokoyama Shigeru、Furuhara Kazumi、Lopatina Olga、Shabalova Anna、Salmina Alla B.、Watanabe Yumi、Hattori Tsuyoshi、Nishimori Katsuhiko、Kodama Kota、Higashida Haruhiro
  • Journal Title: Journal of Neuroendocrinology Volume: - Issue: 4
  • DOI: 10.1111/jne.12815
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Microglial activation in the cochlear nucleus after early hearing loss in rats. (2019)
  • Author(s): Noda M, Hatano M, Hattori T, Takarada-Iemata M, Shinozaki T, Sugimoto H, Ito M, Yoshizaki T, Hori O.
  • Journal Title: Auris Nasus Larynx. Volume: 印刷中 Issue: 5 Pages: 716-723
  • DOI: 10.1016/j.anl.2019.02.006
  • Peer Reviewed / Open Access
• [Journal Article] Pre-administration of low-dose methamphetamine enhances movement and neural activity after high-dose methamphetamine administration in the striatum (2019)
  • Author(s): Takeichi T, Hori O, Hattori T, Kiryu K, Zuka M, Kitamura O
  • Journal Title: Neurosci Lett Volume: 703 Pages: 119-124
  • DOI: 10.1016/j.neulet.2019.03.023
  • Peer Reviewed / Open Access
• [Journal Article] Caspase-1 initiates apoptosis in the absence of gasdermin D (2019)
  • Author(s): Tsuchiya K, Nakajima S, SHosojima S, Nguyen DT, Hattori T, Le TM, Hori O, Mahib MR, Yamaguchi Y, Miura M, Kinoshita T, Kushiyama H, Sakurai M, Shiroishi T, Suda T
  • Journal Title: Nature Communications Volume: In press Issue: 1 Pages: 2091-2091
  • DOI: 10.1038/s41467-019-09753-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Deletion of CD38 Suppresses Glial Activation and Neuroinflammation in a Mouse Model of Demyelination (2019)
  • Author(s): Roboon Jureepon、Hattori Tsuyoshi、Ishii Hiroshi、Takarada-Iemata Mika、Le Thuong Manh、Shiraishi Yoshitake、Ozaki Noriyuki、Yamamoto Yasuhiko、Sugawara Akira、Okamoto Hiroshi、Higashida Haruhiro、Kitao Yasuko、Hori Osamu
  • Journal Title: Frontiers in Cellular Neuroscience Volume: 13 Pages: 258-258
  • DOI: 10.3389/fncel.2019.00258
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CD38, CD157, and RAGE as Molecular Determinants for Social Behavior. (2019)
  • Author(s): .Higashida H, Hashii M, Tanaka Y, Matsukawa S, Higuchi Y, Gabata R, Tsubomoto M, Seishima N, Teramachi M, Kamijima T, Hattori T, Hori O, Tsuji C, Cherepanov SM, Shabalova AA, Gerasimenko M, Minami K, Yokoyama S, Munesue SI, Harashima A, Yamamoto Y, Salmina AB, Lopatina O.
  • Journal Title: Cells. Volume: 9(1) Issue: 1 Pages: 62-62
  • DOI: 10.3390/cells9010062
  • NAID: 120006859506
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] The role of astrocytic CD38 for neuronal development and social memory (2021)
  • Author(s): 服部剛志
  • Organizer: 第126回日本解剖学会総会・全国学術集会 / 第98回日本生理学会大会
• [Presentation] 神経及びグリア発達におけるCD38の役割 (2019)
  • Author(s): 服部 剛志
  • Organizer: CD38研究会
• [Presentation] アストロサイトCD38による神経発達と行動への影響 (2019)
  • Author(s): 服部 剛志
  • Organizer: 第9回自閉症研究会
• [Presentation] アストロサイトCD38による髄鞘化と脱髄化のメカニズム (2019)
  • Author(s): 服部 剛志
  • Organizer: Neuro2019 第４２回日本神経化学大会 第６０回日本神経化学会大会
  • Int'l Joint Research
• [Presentation] 脳発達と社会性行動におけるアストロサイトCD38の役割 (2019)
  • Author(s): 服部 剛志
  • Organizer: 第49回日本神経精神薬理学会
• [Presentation] アストロサイトCD38による神経発達への影響 (2019)
  • Author(s): 服部 剛志
  • Organizer: 第20回 ORIGIN 神経科学研究会
• [Presentation] アストロサイトCD38による神経発達制御機構 (2018)
  • Author(s): 服部 剛志、堀 修
  • Organizer: 日本解剖学会 第78回中部支部学術集会
• [Presentation] 脳発達におけるCD38の役割 (2018)
  • Author(s): 服部 剛志
  • Organizer: Symposium on Neural Orchestration and Islet Biology
  • Invited
• [Presentation] 神経及びグリア発達におけるCD38の役割 (2018)
  • Author(s): 服部 剛志、 堀 修
  • Organizer: 第61回日本神経化学会大会
  • Int'l Joint Research
• [Presentation] The role of astrocytic CD38 for neuronal development (2018)
  • Author(s): Tsuyoshi Hattori, Stanislav M. Cherepanov, Shabalova Anna, Roboon Jureepon, Hiroshi Ishii, Mika Takarada-Iemata, Nguyen Thi Dinh, Hiroshi Okamoto, Yasuhiko Yamamoto, Haruhiro Higashida, Osamu Hori
  • Organizer: International Symposium on NEW FRONTIER in NEUROSCIENCE
  • Int'l Joint Research
• [Presentation] 生後のグリア細胞発達におけるCD38の役割 (2018)
  • Author(s): 服部 剛志
  • Organizer: 第7回自閉症学研究会
• [Remarks] 脳の炎症を抑える分子を発見！
  • URL: https://www.kanazawa-u.ac.jp/wp-content/uploads/2021/04/210428.pdf
• [Remarks] 金沢大学医薬保健研究域 神経解剖学
  • URL: https://med03.w3.kanazawa-u.ac.jp/index.html
• [Remarks] 金沢大学医薬保健研究域医学系 神経解剖学
  • URL: http://med03.w3.kanazawa-u.ac.jp/index.html
• [Remarks] 金沢大学 医薬保健研究域医学系 神経解剖学
  • URL: http://med03.w3.kanazawa-u.ac.jp/event.html#event170127