Understanding for Alzheimer's disease pathogenesis involved in ApoE4 and X11L genes by large scale of expression analysis of genes

• Project/Area Number: 16K14690
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Functional biochemistry
• Research Institution: Hokkaido University
• Principal Investigator: SUZUKI Toshiharu 北海道大学, 薬学研究院, 教授 (80179233)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: アルツハイマー病 / アポリポタンパク質 / 遺伝子発現制御 / ApolipoproteinE / X11-like / 遺伝子 / 脳・神経疾患 / 認知症 / トランスクリプトーム

Outline of Final Research Achievements

ApoE4 is largest risk factor of Alzheimer's disease (AD) except for aging.Resent researches report a alternative gene expression in AD subjects of ApoE4 carriers compared to non-carriers.One of strong candidate to regulate ApoE gene expression is X11L gene that we identified previously. In this research using ApoE4-KI/X11L-KO mice, we analyzed gene-expression profiles, and we identified FXR-binding motif on genes involving in AD onset. Furthermore, we found that X11L regulates ApoE gene expression, which further regulates genes possessing FXR-binding motif, some of them may involve the pathogenesis of AD.

Research Products

• [Int'l Joint Research] Yale University Medical School/Mount Sinai School of Medicine(米国)
• [Int'l Joint Research] ManRos Therapeutics(France)
• [Journal Article] Induction of Amyloid-β42 Production by Fipronil and Other Pyrazole Insecticides (2018)
  • Author(s): Cam M, Durieu E, Bodin M, Manousopoulou A, Koslowski S, Vasylieva N, Barnych B, Hammock BD, Bohl B, Koch P, Omori C, Yamamoto K, Hata S, Suzuki T, Karg F, Gizzi P, Haber VE, Bencetic Mihaljevic V, Tavcar B, Portelius E, Pannee J, Blennow K, Zetterberg H, Garbis SD, Auvray P, Gerber H, Fraering J, Fraering PC, Meijer L.
  • Journal Title: Journal of Alzheimer's Disease Volume: 62 Issue: 4 Pages: 1663-1681
  • DOI: 10.3233/jad-170875
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Phosphorylation of KLC1 modifies interaction with JIP1 and abolishes the enhanced fast velocity of APP transport by kinesin-1 (2017)
  • Author(s): Chiba Kyoko、Chien Ko-yi、Sobu Yuriko、Hata Saori、Kato Shun、Nakaya Tadashi、Okada Yasushi、Nairn Angus C.、Kinjo Masataka、Taru Hidenori、Wang Rong、Suzuki Toshiharu
  • Journal Title: Molecular Biology of the Cell Volume: 28 Issue: 26 Pages: 3857-3869
  • DOI: 10.1091/mbc.e17-05-0303
  • NAID: 120006394566
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Phosphorylation of multiple sites within an acidic region of Alcadein α is required for kinesin-1 association and Golgi exit of Alcadein α cargo (2017)
  • Author(s): Sobu Yuriko、Furukori Keiko、Chiba Kyoko、Nairn Angus C.、Kinjo Masataka、Hata Saori、Suzuki Toshiharu
  • Journal Title: Molecular Biology of the Cell Volume: 28 Issue: 26 Pages: 3844-3856
  • DOI: 10.1091/mbc.e17-05-0301
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Facilitation of brain mitochondrial activity by 5-aminolevulinic acid in a mouse model of Alzheimer's disease (2017)
  • Author(s): Chiori Omori, Rika Motodate, Yuzuha Shiraki, Kyoko Chiba, Yuriko Sobu, Ayano Kimura, Tadashi Nakaya, Hikaru Kondo, Satoshi Kurumiya, Toru Tanaka, Kazuo Yamamoto, Motowo Nakajima, Toshiharu Suzuki and Saori Hata
  • Journal Title: Nutritional neuroscience Volume: 印刷中 Issue: 9 Pages: 538-546
  • DOI: 10.1080/1028415x.2016.1199114
  • Peer Reviewed / Open Access
• [Journal Article] Expression and localization of X11 family proteins in neurons (2016)
  • Author(s): Motodate, R., Saito, Y., Hata, S., Suzuki, T.
  • Journal Title: Brain Res Volume: 1646 Pages: 227-234
  • DOI: 10.1016/j.brainres.2016.05.054
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Specific triazine herbicides induce amyloidβ42 production. (2016)
  • Author(s): Portlius E, Durieu E, Bodin M, Cam M, Pannee J, Leuxe C, Mabondzo A, Oumata N, Galons H, Lee J-Y, Chang Y-T, Stuber K, Koch P, Fontanine G, Potier M, Manouspoulou A, Garbis S, Covaci A, VanDam D, De Deyn P, Karg F, Flajolet M, Omori C, Hata S, Suzuki T, Blennow K, Zetteberg H, and Meijer L
  • Journal Title: J. Alzheimer Dis Volume: 54 Issue: 4 Pages: 1593-1605
  • DOI: 10.3233/jad-160310
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Altered cortical dynamics and cognitive function upon haploinsufficiency of the autism-linked excitatory synaptic suppressor MDGA2 (2016)
  • Author(s): S. A. Connor, I. Ammendrup-Johnsen, A. W. Chan, Y. Kishimoto, C. Murayama, N. Kurihara, A. Tada, Y. Ge, H. Lu, R. Yan, J. M. LeDue, H. Matsumoto, H. Kiyonari, Y. Kirino, F. Matsuzaki, T. Suzuki, T. H. Murphy, Y. T. Wang, T. Yamamoto, A. M. Craig
  • Journal Title: Neuron Volume: 91 Issue: 5 Pages: 1052-1068
  • DOI: 10.1016/j.neuron.2016.08.016
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Alternative Selection of BACE1 Cleavage Sites in APP Harboring Protective And Pathogenic Mutations Within the Aβ Sequence (2016)
  • Author(s): Kimura, A., Hata, S., Suzuki, T
  • Journal Title: J. Biol. Chem. Volume: 291 Issue: 46 Pages: 24041-24053
  • DOI: 10.1074/jbc.m116.744722
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Enhanced fast velocity of APP transport by kinesin-1 is regulated by KLC1 phosphorylation (2017)
  • Author(s): Kato S, Chiba K, Sobu Y, Chien K-Y, Wang R, Nairn AC, Kinjo M, Hata S, Suzuki T.
  • Organizer: ASCB/EMBO 2017 meeting
  • Int'l Joint Research
• [Presentation] Phosphorylation of multiple sites of Alcadein alpha is required for kinesin-1 association and Golgi exit of Alcadein α (2017)
  • Author(s): Sobu Y, Nairn AC, Kinjo M, Hata S, Suzuki T.
  • Organizer: ASCB/EMBO 2017 meeting
  • Int'l Joint Research
• [Presentation] A novel biomarker p3-Alcα, peptides produced by γ-secretase cleavage, altered in Alzheimer’s patients. (2017)
  • Author(s): Omori C., Waragai M., Suzuki T., Yamamoto K.
  • Organizer: Alzheimer's Association International Conference 2017
  • Int'l Joint Research
• [Presentation] Protective property of p3-Alcβ against a neurotoxicity induced by Aβ oligomer. (2017)
  • Author(s): Saitoh H., Omori C., Kimura Y., Waragai M., Maeda M., Hata S., Suzuki T.
  • Organizer: Alzheimer's Association International Conference 2017
  • Int'l Joint Research
• [Presentation] Identification of ApoE4-X11L Regulated Down Stream Genes Related to the Late-Onset AD (2017)
  • Author(s): Toyoda M. , Nakaya T. , Michikawa M. , Suzuki T.
  • Organizer: Alzheimer's Association International Conference 2017
  • Int'l Joint Research
• [Presentation] Level of of p3-Alcβ peptides alter in CSF of Alzheimer’s patients (2017)
  • Author(s): Hata S., Kimura Y., Waragai M., Ikeuchi T., Martins R., Kimura N., Nishimura M., Suzuki T.
  • Organizer: Alzheimer's Association International Conference 2017
  • Int'l Joint Research
• [Presentation] Regulation and function of APP as a cargo receptor of kinesin-1 in neuron. (2017)
  • Author(s): Suzuki T., Chiba K, Shiraki Y, Sobu Y, Hata S.
  • Organizer: Alzheimer's Association International Conference 2017
  • Int'l Joint Research
• [Presentation] ApoE4存在下でのX11L下流遺伝子発現変化 (2016)
  • Author(s): 豊田めぐみ、羽田沙緒里、道川誠、中矢正、鈴木利治
  • Organizer: 第35回日本認知症学会学術集会
  • Place of Presentation: 東京国際フォーラム （東京都千代田区）
  • Year and Date: 2016-12-01
  • Int'l Joint Research
• [Presentation] Aβ oligomer による神経毒性を抑制する内在性p3-Alcβペプチドの体内動態と機能 (2016)
  • Author(s): 斎藤遥、大森智織、木村彩乃、内山藍、熊谷久美子、西尾秀喜、前田雅弘、羽田沙緒里、鈴木利治
  • Organizer: 第35回日本認知症学会学術集会
  • Place of Presentation: 東京国際フォーラム （東京都千代田区）
  • Year and Date: 2016-12-01
  • Int'l Joint Research
• [Presentation] X11 and X11L regulate the non-synaptic NMDA receptor localization. (2016)
  • Author(s): Rika Motodate, Yuhki Saito, Toshiharu Suzuki.
  • Organizer: Neuroscience 2016
  • Place of Presentation: San Diego (USA)
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Aberrant micro-membrane localization of g-secretase components by changes in cellular cholesterol level alters e- and/or g-cleavage of APP and Alcadeina (2016)
  • Author(s): Hu Anqi, Yi Piao, Saori Hata, Toshiharu Suzuki
  • Organizer: AAIC 2016
  • Place of Presentation: Toronto (Canada)
  • Year and Date: 2016-07-24
  • Int'l Joint Research
• [Presentation] Increase of p3-Alca38 to p3-Alca35, products of alcadeinaby g-secretase cleavage, in CSF of AD patients (2016)
  • Author(s): Chioti Omori, Saori Hata, Masaaki Waragai, Kazuo Yamamoto, Toshiharu Suzuki
  • Organizer: AAIC 2016
  • Place of Presentation: Toronto (Canada)
  • Year and Date: 2016-07-24
  • Int'l Joint Research
• [Presentation] Alternative cleavage mechanism of human BACE1 (2016)
  • Author(s): Toshiharu Suzuki, Ayano Kimura, Saori Hata
  • Organizer: AAIC 2016
  • Place of Presentation: Toronto (Canada)
  • Year and Date: 2016-07-24
  • Int'l Joint Research
• [Remarks]
  • URL: http://www.pharm.hokudai.ac.jp/shinkei/index.html