The mechnisms of physiological exosome delivery to neurons

• Project/Area Number: 18K06456
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 46010:Neuroscience-general-related
• Research Institution: Hokkaido University
• Principal Investigator: Yuyama Kohei 北海道大学, 先端生命科学研究院, 特任准教授 (80415546)
• 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: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: エクソソーム / ミクログリア / ニューロン / 糖鎖 / アルツハイマー病 / アミロイドbeta / 細胞外小胞 / Abeta / 神経細胞

Outline of Final Research Achievements

In brains, the exosomes, a type of extracellular vesicles, released from microglia contain tau protein, a pathogenic agent of Alzheimer's disease, and transport them into neurons, contributing pathogenesis of the disease. However, the molecular mechanism for exosome targeting to neurons remains unclear. In this study, I found that a specific sialic acid-containing sugar chain of glycoprotein was involved in the transport of microglia-derived exosomes to neurons.

Academic Significance and Societal Importance of the Research Achievements

細胞外小胞の神経細胞間移行はアルツハイマー病のタウ病理をはじめとして神経変性疾患の病理形成に関与しているとの報告がある。本研究で明らかとなった細胞外小胞の神経ターゲティング因子候補は現在根本治療法のないアルツハイマー病の病理形成機構の解明につながる成果であり、アルツハイマー病の予防・治療法開発に応用できる可能性がある。また当該糖鎖含有人工リポソームの作製は新たな脳神経をターゲットとしたドラッグデリバリーシステム開発への応用も考えられる。

Research Products

• [Journal Article] Glucocerebrosidases catalyze a transgalactosylation reaction that yields a newly-identified brain sterol metabolite, galactosylated cholesterol (2020)
  • Author(s): Akiyama, H., Ide, M., Nagatsuka, Y., Sayano, T., Nakanishi, E., Uemura, N., Yuyama, K., Yamaguchi, Y., Kamiguchi, H., Takahashi, R., Aerts, J. M. F. G., Greimel, P. and Hirabayashi, Y
  • Journal Title: Journal of Biological Chemistry Volume: 295 Issue: 16 Pages: 5257-5277
  • DOI: 10.1074/jbc.ra119.012502
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lysosomal‐associated transmembrane protein 4B regulates ceramide‐induced exosome release (2020)
  • Author(s): Yuyama Kohei、Sun Hui、Mikami Daisuke、Mioka Tetsuo、Mukai Katsuyuki、Igarashi Yasuyuki
  • Journal Title: The FASEB Journal Volume: 34 Issue: 12 Pages: 16022-16033
  • DOI: 10.1096/fj.202001599r
  • Peer Reviewed
• [Journal Article] Nrp1 is Activated by Konjac Ceramide Binding-Induced Structural Rigidification of the a1a2 Domain (2020)
  • Author(s): Usuki Seigo、Yasutake Yoshiaki、Tamura Noriko、Tamura Tomohiro、Tanji Kunikazu、Saitoh Takashi、Murai Yuta、Mikami Daisuke、Yuyama Kohei、Monde Kenji、Mukai Katsuyuki、Igarashi Yasuyuki
  • Journal Title: Cells Volume: 9 Issue: 2 Pages: 517-517
  • DOI: 10.3390/cells9020517
  • Peer Reviewed / Open Access
• [Journal Article] Plant sphingolipids promote extracellular vesicle release and alleviate amyloid-β pathologies in a mouse model of Alzheimer’s disease (2019)
  • Author(s): Yuyama Kohei、Takahashi Kaori、Usuki Seigo、Mikami Daisuke、Sun Hui、Hanamatsu Hisatoshi、Furukawa Junichi、Mukai Katsuyuki、Igarashi Yasuyuki
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 16827-16827
  • DOI: 10.1038/s41598-019-53394-w
  • Peer Reviewed / Open Access
• [Journal Article] Malabaricone C as Natural Sphingomyelin Synthase Inhibitor against Diet-Induced Obesity and Its Lipid Metabolism in Mice (2019)
  • Author(s): Othman Muhamad Aqmal、Yuyama Kohei、Murai Yuta、Igarashi Yasuyuki、Mikami Daisuke、Sivasothy Yasodha、Awang Khalijah、Monde Kenji
  • Journal Title: ACS Medicinal Chemistry Letters Volume: 10 Issue: 8 Pages: 1154-1158
  • DOI: 10.1021/acsmedchemlett.9b00171
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Extracellular Vesicles from Amnion-Derived Mesenchymal Stem Cells Ameliorate Hepatic Inflammation and Fibrosis in Rats (2018)
  • Author(s): Ohara Masatsugu、Ohnishi Shunsuke、Hosono Hidetaka、Yamamoto Koji、Yuyama Kohei、Nakamura Hideki、Fu Qingjie、Maehara Osamu、Suda Goki、Sakamoto Naoya
  • Journal Title: Stem Cells International Volume: 2018 Pages: 1-15
  • DOI: 10.1155/2018/3212643
  • NAID: 120006585982
  • Peer Reviewed / Open Access
• [Journal Article] Multiple roles of SMS2 in white and brown adipose tissues form diet-induced obese mice (2018)
  • Author(s): H. Hamamatsu, S. Mitsutake, S. Sakai, T. Okazaki, K. Watanabe, Y. Igarashi, K. Yuyama
  • Journal Title: J. Metabolic Syndrome Volume: 7 Issue: 02 Pages: 241-241
  • DOI: 10.4172/2167-0943.1000241
  • Peer Reviewed / Open Access
• [Journal Article] Konjac Ceramide (kCer) Regulates NGF-Induced Neurite Outgrowth via the Sema3A Signaling Pathway (2018)
  • Author(s): Usuki Seigo、Tamura Noriko、Yuyama Kohei、Tamura Tomohiro、Mukai Katsuyuki、Igarashi Yasuyuki
  • Journal Title: Journal of Oleo Science Volume: 67 Issue: 1 Pages: 77-86
  • DOI: 10.5650/jos.ess17141
  • NAID: 130006301047
  • ISSN: 1345-8957, 1347-3352
  • Peer Reviewed
• [Presentation] セラミドによるエクソソーム産生誘導とその神経疾患関連機能 (2019)
  • Author(s): 湯山耕平
  • Organizer: 第12回セラミド研究会学術集会
  • Invited
• [Presentation] こんにゃくセラミドによるエクソソームを介した 脳内アミロイドbetaの除去メカニズム (2019)
  • Author(s): 湯山耕平
  • Organizer: 第73回日本栄養・食糧学会大会
  • Invited
• [Presentation] Dietary ceramides in skin and brain health (2019)
  • Author(s): Kohei Yuyama
  • Organizer: 7th International Conference on Food Factors (ICoFF2019)
  • Int'l Joint Research / Invited