Sulf2-remodeling of heparan sulfate present in brain amyloids

• Project/Area Number: 15K08265
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Nagoya University
• Principal Investigator: UCHIMURA Kenji 名古屋大学, 医学系研究科, 招へい教員 (20450835)
• Co-Investigator(Kenkyū-buntansha): 門松 健治 名古屋大学, 医学系研究科, 教授 (80204519)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 糖鎖 / 酵素 / 生体分子 / 脳神経疾患

Outline of Final Research Achievements

Extracellular accumulation of amyloid beta peptides is a character of cerebral amyloid plaques in Alzheimer's disease. Heparan sulfate is an extracellular carbohydrate chain found in amyloid plaques in the brain of transgenic Alzheimer's model mice and patients with Alzheimer's disease. Highly sulfated subdomains within heparan sulfate chains are abundant in amyloid plaques of Alzheimer's mouse brains. Degradation of these subdomains may be a potential approach to activate microglial clearance of the plaques in Alzheimer's brain. We tested if the transgenic expression of an extracellular sulfatase in Alzheimer's model mice could facilitate removal of the subdomains and attenuate cerebral amyloid plaque formation. We have shown that a cell type-specific expression of an extracellular sulfatase resulted in negative regulation of amyloid plaque formation. An enzymatic remodeling of extracellular heparan sulfates in the brain can perhaps control Alzheimer’s pathogenesis.

Research Products

• [Int'l Joint Research] カリフォルニア大学サンフランシスコ校(米国)
• [Int'l Joint Research] 中央研究院(台湾)
• [Int'l Joint Research] カリフォルニア大学サンフランシスコ校(米国)
• [Int'l Joint Research] 中央研究院(台湾)
• [Journal Article] Enzymatic Remodeling of Heparan Sulfate: A Therapeutic Strategy for Systemic and Localized Amyloidoses? (2016)
  • Author(s): Nishitsuji K. Saito H., and Uchimura K.
  • Journal Title: Neur. Regener. Res. Volume: 11 Issue: 3 Pages: 408-409
  • DOI: 10.4103/1673-5374.179043
  • Peer Reviewed / Open Access
• [Journal Article] Enthalpy-driven interactions with sulfated glycosaminoglycans promote cell membrane penetration of arginine peptides. (2016)
  • Author(s): Takechi-Haraya Y, Nadai R, Kimura H, Nishitsuji K, Uchimura K, Sakai-Kato K, Ka-wakami K, Shigenaga A, Kawakami T, Otaka A, Hojo H, Sakashita N, Saito H
  • Journal Title: Biochimica et Biophysica Acta Volume: - Issue: 6 Pages: 1339-1349
  • DOI: 10.1016/j.bbamem.2016.03.021
  • Peer Reviewed
• [Journal Article] Reduced molecular size and altered disaccharide composition of cerebral chondroitin sulfate upon Alzheimer's pathogenesis in mice. (2016)
  • Author(s): Zhang, Z., Ohtake-Niimi, S., Kadomatsu, K. and Uchimura, K.
  • Journal Title: Nagoya J. Med. Sci. Volume: 78 Pages: 293-301
  • NAID: 120005837931
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Iowa Mutant Apolipoprotein A-I (ApoA-IIowa) Fibrils Target Lysosomes. (2016)
  • Author(s): Kameyama H., Nakajima H., Nishitsuji K., Mikawa S., Uchimura K., Kobayashi N., Okuhira K., Saito H., and Sakashita N.
  • Journal Title: Sci. Rep. Volume: 6 Issue: 1 Pages: 30391-30391
  • DOI: 10.1038/srep30391
  • NAID: 120006534966
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The polyphenol (-)-epigallocatechin-3-gallate prevents apoA-IIowa amyloidosis in vitro and protects human embryonic kidney 293 cells against amyloid cytotoxicity. (2016)
  • Author(s): Nakajima H, Nishitsuji K, Kawashima H, Kuwabara K, Mikawa S, Uchimura K, Akaji K, Kashiwada Y, Kobayashi N, Saito H, Sakashita N
  • Journal Title: Amyloid Volume: 23 Issue: 1 Pages: 17-25
  • DOI: 10.3109/13506129.2015.1113167
  • Peer Reviewed
• [Journal Article] Cellular Interaction and Cytotoxicity of the Iowa Mutation of Apolipoprotein A-I (ApoA-IIowa) Amyloid Mediated by Sulfate Moieties of Heparan Sulfate (2015)
  • Author(s): Kuwabara, K., Nishitsuji, K., Uchimura, K., Hung, S.C., Mizuguchi, M., Nakajima, H., Mikawa, S., Kobayashi, N., Saito, H., and Sakashita, N.
  • Journal Title: J Biol Chem Volume: 290 Issue: 40 Pages: 24210-24221
  • DOI: 10.1074/jbc.m115.652545
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Microglial keratan sulfate epitope elicits in central nervous tissues of transgenic model mice and patients with amyotrophic lateral sclerosis. (2015)
  • Author(s): Foyez T, Takeda-Uchimura Y, Ishigaki S, Narentuya, Zhang Z, Sobue G, Kadomatsu K, Uchimura K.
  • Journal Title: Am J Pathol Volume: 185 Issue: 11 Pages: 3053-3065
  • DOI: 10.1016/j.ajpath.2015.07.016
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Gene disruption of GlcNAc 6-O-sulfotransferase-1 results in loss of microglial keratan sulfate and alleviation of Alzheimer's pathogenesis in mice (2015)
  • Author(s): Zui Zhang, Yoshiko Uchimura, Tahmina Foyez, Shiori Niimi, Hitomi Hoshino, Tomomi Hosono, Makoto Michikawa, Kenji Kadomatsu and Kenji Uchimura
  • Organizer: 第３８回分子生物学会年会第８８回日本生化学会大会合同年会
  • Place of Presentation: 神戸ポートアイランド（兵庫県神戸市）
  • Year and Date: 2015-12-03
• [Presentation] 神経回路再編および神経変性に関わるケラタン硫酸 (2015)
  • Author(s): 内村健治、門松健治
  • Organizer: 第３４回日本糖質学会
  • Place of Presentation: 東京大学（東京都文京区）
  • Year and Date: 2015-08-02
• [Remarks] 教室HPアドレス
  • URL: http://www.med.nagoya-u.ac.jp/biochem/