Role of glycosylation in processing of APP

• Project/Area Number: 26460090
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology
• Principal Investigator: Manya Hiroshi 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, 研究副部長 (20321870)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 糖鎖 / 脳神経疾患 / 老化 / アルツハイマー病 / アミロイド前駆体タンパク質

Outline of Final Research Achievements

Alterations of the structure or amount of glycans on glycoproteins are associated with many diseases. We previously demonstrated that changes in N-glycans alter Aβ production. Here, we focused on the relationship between Alzheimer’s disease (AD) and O-glycan. The polypeptide N-acetylgalactosaminyltransferase (GALNT) family functions in the first step of mucin-type O-glycan synthesis. Analysis of the expression of GALNTs in the human brain using real-time PCR revealed that the expression of several GALNTs were altered with sporadic AD progression. The expression of GALNT6 increased in AD brain. Transfection of GALNT6 significantly reduced both Aβ40 and Aβ42 secretion. GALNT6 exhibited GalNAc transferase activity on amyloid precursor protein (APP). The activities of α-secretase and β-secretase were not significantly altered in the transfected cells. These data suggest that excess O-glycosylation on APP by GALNT6 inhibits Aβ production.

Research Products

• [Journal Article] Excess APP O-glycosylation by GalNAc-T6 decreases Aβ production. (2017)
  • Author(s): Keiko Akasaka-Manya, Masaki Kawamura, Hiroki Tsumoto, Yuko Saitoh, Yuriko Tachida, Shinobu Kitazume, Hiroyuki Hatsuta, Yuri Miura, Shin-ichi Hisanaga, Shigeo Murayama, Yasuhiro Hashimoto, Hiroshi Manya, Tamao Endo
  • Journal Title: J. Biochem. Volume: 161 Issue: 1 Pages: 99-111
  • DOI: 10.1093/jb/mvw056
  • NAID: 40021091544
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] An aberrant sugar modification of BACE1 blocks its lysosomal targeting in Alzheimer’s disease (2015)
  • Author(s): Yasuhiko Kizuka, Shinobu Kitazume, Reiko Fujinawa, Takashi Saito, Nobuhisa Iwata, Takaomi C. Saido, Miyako Nakano, Yoshiki Yamaguchi, Yasuhiro Hashimoto
  • Journal Title: EMBO Mol. Med. Volume: 7(2) Issue: 2 Pages: 175-89
  • DOI: 10.15252/emmm.201404438
  • NAID: 120006799362
  • Peer Reviewed / Open Access
• [Journal Article] Major glycan structure underlying expression of the Lewis X epitope in the developing brain is O-mannose-linked glycans on phosphacan/RPTPβ (2015)
  • Author(s): Shohei Yaji, Hiroshi Manya, Naoki Nakagawa, Hiromu Take matsu, Tamao Endo, Reiji Kannagi, Toru Yoshihara, Masahide Asano, Shogo Oka
  • Journal Title: Glycobiology Volume: 25 Issue: 4 Pages: 376-385
  • DOI: 10.1093/glycob/cwu118
  • Peer Reviewed / Open Access
• [Presentation] APP代謝におけるO型糖鎖修飾の影響 (2017)
  • Author(s): 赤阪-萬谷啓子、萬谷博、遠藤玉夫
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 仙台国際センター（宮城県・仙台市）
  • Year and Date: 2017-03-24
• [Presentation] Aβ産生におけるO型糖鎖修飾の影響 (2016)
  • Author(s): 赤阪-萬谷啓子、川村方希、津元裕樹、萬谷博、遠藤玉夫
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2016-11-30
• [Presentation] APP代謝におけるppGalNAcT-6の影響 (2016)
  • Author(s): 赤阪-萬谷啓子、川村方希、津元裕樹、萬谷博、遠藤玉夫
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター（宮城県・仙台市）
  • Year and Date: 2016-09-25
• [Presentation] アミロイド産生と脳アミロイドアンギオパチーを規定する血管内皮細胞のO-GalNAc型糖鎖 (2016)
  • Author(s): 北爪しのぶ、立田由里子、木塚康彦、今牧理恵、加藤雅樹、山口芳樹、田中克典、中の三弥子、斎藤貴志、西道隆臣、萬谷博、遠藤玉夫、橋本康弘、谷口直之
  • Organizer: 第34回日本糖質学会年会
  • Place of Presentation: 高知市文化プラザ かるぽーと（高知県・高知市）
  • Year and Date: 2016-09-01
• [Presentation] O型糖鎖修飾によるAPP代謝への影響 (2016)
  • Author(s): 赤阪-萬谷啓子、川村方希、萬谷博、遠藤玉夫
  • Organizer: 第39回日本基礎老化学会大会
  • Place of Presentation: 伊勢原市民文化会館（神奈川県・伊勢原市）
  • Year and Date: 2016-05-27
• [Presentation] α-Klothoの欠損による糖鎖異常 (2015)
  • Author(s): 生形亮介、赤阪啓子、萬谷博、遠藤玉夫
  • Organizer: 首都大バイオコンファレンス2015
  • Place of Presentation: 首都大学東京（東京都・八王子市）
  • Year and Date: 2015-11-06
• [Presentation] 老化に伴って増加する非硫酸化グルクロン酸によるCD13の活性変化 (2015)
  • Author(s): 赤阪-萬谷啓子、萬谷博、岡昌吾、遠藤玉夫
  • Organizer: 第34回日本糖質学会年会
  • Place of Presentation: 東京大学（東京都・文京区）
  • Year and Date: 2015-07-31
• [Presentation] 組換え糖転移酵素POMGnT1のO-結合型糖鎖解析 (2015)
  • Author(s): 津元裕樹、萬谷博、遠藤玉夫、三浦ゆり
  • Organizer: 日本質量分析学会第63回質量分析総合討論会
  • Place of Presentation: つくば国際会議場（茨城県・つくば市）
  • Year and Date: 2015-06-17
• [Presentation] O型糖鎖修飾によるアミロイドβ産生への影響. (2014)
  • Author(s): 川村方希、赤阪-萬谷啓子、萬谷博、櫻井洋子、遠藤玉夫
  • Organizer: 首都大学東京バイオコンファレンス2014
  • Place of Presentation: 東京
  • Year and Date: 2014-11-07
• [Presentation] アルツハイマー病患者の脳における糖転移酵素の発現解析 (2014)
  • Author(s): 萬谷博、赤阪-萬谷啓子、遠藤玉夫
  • Organizer: 第33回日本糖質学会年会
  • Place of Presentation: 名古屋
  • Year and Date: 2014-08-10 – 2014-08-12
  • Invited
• [Presentation] Bisecting GlcNAc欠損によるアルツハイマー病抑制に関する研究 (2014)
  • Author(s): 木塚康彦、北爪しのぶ、藤縄玲子、斉藤貴志、岩田修永、西道隆臣、中の三弥子、山口芳樹、橋本康弘、Matthias Staufenbiel、初田裕幸、村山繁雄、萬谷博、遠藤玉夫、谷口直之
  • Organizer: 第33回日本糖質学会年会
  • Place of Presentation: 名古屋
  • Year and Date: 2014-08-10 – 2014-08-12
• [Book] Sugar chains (2015)
  • Author(s): Manya, H., Endo, T.
  • Total Pages: 288
  • Publisher: Springer
• [Book] Handbook of Glycosyl transferases and related genes (2014)
  • Author(s): Manya, H., Endo, T.
  • Total Pages: 670
  • Publisher: Springer