The role of ATBF1 in APP metabolism and A beta production

• Project/Area Number: 24500402
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neuroscience in general
• Research Institution: Nagoya City University
• Principal Investigator: JUNG Cha-Gyun 名古屋市立大学, 医学(系)研究科(研究院), 准教授 (00464579)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: アルツハイマー病 / ATBF1 / APP代謝 / Aβ産生

Outline of Final Research Achievements

ATBF1 levels are increased in the cytoplasm of hippocampal neurons in Alzheimer’s disease (AD) brains compared with non-AD brains. Furthermore, cotransfection of human embryonic kidney (HEK293T) and human neuroblastoma (SH-SY5Y) cells with ATBF1 and APP695 increased steady-state levels of APP via the binding of ATBF1 to the APP cytoplasmic domain (amino acids 681-690 domain), resulting in increased Aβ production and cellular and soluble APP (sAPP) levels without affecting the activity or levels of APP processing enzymes (α-, β- or γ-secretase). Conversely, knockdown of endogenous ATBF1 reduced levels of cellular APP, sAPP and Aβ in HEK293 cells overexpressing human APP695. Our findings provide insight into the dynamics of APP processing and Aβ production, and suggest that ATBF1 is a novel APP binding protein that may be a suitable therapeutic target for AD.

Research Products

• [Journal Article] Auraptene increases the production of amyloid-beta via c-Jun N-terminal kinase-dependent activation of γ-secretase. (2015)
  • Author(s): Jung CG, Uhm KO, Horike H, Kim MJ, Misumi S, Ishida A, Ued Y, Choi EK, Kim YS, Michikawa M, Hida H.
  • Journal Title: J Alzheimers Dis Volume: 43 Issue: 4 Pages: 1215-1228
  • DOI: 10.3233/jad-141692
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] ATBF1 is a novel amyloid-β protein precursor protein (AβPP) binding protein that affects APP expression (2015)
  • Author(s): Uhm KO, Kim MJ, Kawaguchi M, Akatsu H, Miura Y, Misumi S, Hida H, Choi EK, Kim YS, Michikawa M, Jung CG.
  • Journal Title: J Alzheimers Dis Volume: 43 Issue: 1 Pages: 243-257
  • DOI: 10.3233/jad-140612
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Tooth loss might not alter molecular pathogenesis in an aged transgenic Alzheimer's disease model mouse (2015)
  • Author(s): Oue H, Miyamoto Y, Koretake K, Okada S, Doi K, Jung CG, Michikawa M and Akagawa Y
  • Journal Title: Gerodontology Volume: in press Issue: 3 Pages: 308-14
  • DOI: 10.1111/ger.12153
  • Peer Reviewed
• [Journal Article] Enhanced electrical responsiveness in the cerebral cortex with oral melatonin administration (2014)
  • Author(s): Ueda Y, Masuda T, Ishida A, Misumi S, Shimizu Y, Jung CG, Hida H
  • Journal Title: J Neurosci. Res Volume: 92 Issue: 11 Pages: 1499-1508
  • DOI: 10.1002/jnr.23434
  • Peer Reviewed
• [Journal Article] Differentiation of oligodendrocytes from mouse induced pluripotent stem cells without serum (2013)
  • Author(s): Misumi S, Nishigaki R, Ueda Y, Watanabe Y, Shimizu Y, Ishida A, Jung CG, Hida H
  • Journal Title: Transl Stroke Res Volume: 4(2) Issue: 2 Pages: 149-157
  • DOI: 10.1007/s12975-012-0250-1
  • Peer Reviewed
• [Journal Article] Tooth loss induces memory impairment and neuronal cell loss in APP transgenic mice. (2013)
  • Author(s): Oue H, Miyamoto Y, Okada S, Koretake K, Jung CG, Michikawa M, Akagawa Y.
  • Journal Title: Behav Brain Res. Volume: 252(1) Pages: 318-325
  • DOI: 10.1016/j.bbr.2013.06.015
  • Peer Reviewed
• [Presentation] ATBF1 is a novel amyloid-β precursor protein binding protein that affects amyloid-β production. (2014)
  • Author(s): Jung CG, Uhm KO, Kim MJ, Kawaguchi M, Akatsu H, Miura Y, Misumi S, Choi EK, Kim YS, Michikawa M, Hida H
  • Organizer: Society for Neuroscience, USA
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] Cell death and arrest of lineage progression to oligodendrocyte are followed by indirect damage of corticospinal neurons in the developing white matter injury model rat (2014)
  • Author(s): Misumi S, Ueda Y, Shimizu Y, Jung CG, Hida H.
  • Organizer: Society for Neuroscience, USA
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] Response to intracortical microstimulation in the hindlimb area in the developmental white matter injury model rat (2014)
  • Author(s): Ueda Y, Misumi S, Ishida A, Shimizu Y, Jung CG, Hida H
  • Organizer: Society for Neuroscience, USA
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] Oral intake of monosodium glutamate during the period of development effects on social hevavior mediated by gut-brain communicateon in an ADHD model rat (2014)
  • Author(s): Hida H, Yokoyama Y, Marutomoto R, Shimizu Y, Ueda Y, Misumi S, Ishida A, Jung CG.
  • Organizer: Society for Neuroscience, USA
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] Cocain-and amphetamine-regulated transcript in the central nucleus of amygdala is enhanced by environmental enriched in ADHD model rat (2014)
  • Author(s): Shimizu Y, Yokoyama Y, Misumi S, Ishida A, Jung CG, Hida H
  • Organizer: Society for Neuroscience, USA
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] 脳室周囲白質障害モデルラットにおける皮質脊髄路ニューロンの軽微な傷害 (2014)
  • Author(s): 三角 吉代,上田 佳朋,清水 由布子,石田 章真,鄭 且均,飛田 秀樹
  • Organizer: 第３７回日本神経科学大会
  • Place of Presentation: パシフィコ横浜（神奈川県）
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] Aurapten increases the production of beta amyloid by increasing gamma-secretase activity (2013)
  • Author(s): Jung CG, Horike H, Uhm KO, Misumi S, Hida H, Michikawa M.
  • Organizer: Neuro2013
  • Place of Presentation: 国立京都国際会館（京都）
• [Presentation] ATBF1 KOマウスにおける血管平滑筋細胞の形成不全 (2013)
  • Author(s): 鄭 且均、川口 誠、三浦 裕、飛田秀樹、道川 誠。
  • Organizer: 第６０回中部日本生理学会
  • Place of Presentation: 岐阜大学医学部記念会館ホール（岐阜
• [Presentation] 飼育環境温度変化によるAPP-Tgマウス脳内Aβ代謝への影響 (2013)
  • Author(s): 布目真梨、加藤玲子、榎本啓行、鄭 且均、山下 均、道川 誠。
  • Organizer: 第３２回日本認知症学会
  • Place of Presentation: キッセイ文化ホール（長野県松本文化会館）（松本）
• [Presentation] Hypoplasia of the vascular smooth muscle cell in the ATBF1 KO mouse (2013)
  • Author(s): Jung CG, Kawaguchi M, Miura Y, Hida H, Michikawa M.
  • Organizer: 第９１回日本生理学会
  • Place of Presentation: 鹿児島大学（鹿児島）
• [Presentation] Effect of ATBF1 on APP processing and Aβ production (2013)
  • Author(s): Jung CG, Uhm KO, Kim MJ, Kawaguchi M, Akatsu H, Hida H, Michikawa M.
  • Organizer: 第90回日本生理学会大会
  • Place of Presentation: （タワーホール船堀）東京
• [Presentation] Induction of oligodendrocyte progenitors from mouse iPS cells for transplantation to neonatal white matter injury (2013)
  • Author(s): Sachiyo Misumi, Cha-Gyun Jung, Hideki Hida
  • Organizer: 第90回日本生理学会大会
  • Place of Presentation: （タワーホール船堀）東京
• [Presentation] Blood flow of the prefrontal cortex was increased by stepping on 3-D high repulsion cushion (3-D HRC) (2013)
  • Author(s): Motoyuki Shiraki, Tomoyuki Yamauchi, Susumu Urakawa, Cha-Gyun Jung, Hideki Hida, Hisao Nishijo, Taketoshi Ono and Hitoo Nishino
  • Organizer: 第90回日本生理学会大会
  • Place of Presentation: （タワーホール船堀）東京