Study of pathological protein phosphorylation changes in early-phase Alzheimer's disease

• Project/Area Number: 16K07040
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: TAGAWA Kazuhiko 東京医科歯科大学, 難治疾患研究所, 准教授 (80245795)
• Research Collaborator: OKAZAWA Hitoshi ; FUJITA Keita
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: アルツハイマー病 / 超早期病態 / MARCKS / SRRM2 / タウ / アミロイドβ / 神経変性疾患 / 早期病態 / HMGB1 / PQBP1 / リン酸化プロテオーム / GAPDH / 過食 / リン酸化プロテオーム解析 / 神経科学 / 脳神経疾患 / 痴呆 / プロテオーム / シグナル伝達

Outline of Final Research Achievements

Alzheimer’s disease (AD) is defined by extracellular beta amyloid (Aβ) aggregates in human pathology. Therapeutic drugs were developed with the aim of removing extracellular Aβ aggregates. However, clinical trials of drugs designed to remove Aβ aggregates failed to recover memory and cognitive function in symptomatic AD patients. Our previous work, we found that the phosphorylation status of AD pathological proteins changes on phosphoproteome study in early phase of AD. We reported the molecular pathology of MARCKS and SRRM2 in AD. And our findings revealed a new tau phosphorylation-dependent mechanism in the pathology of non-tau FTLD (frontotemporal lobar degeneration) as common pathology with AD.

Academic Significance and Societal Importance of the Research Achievements

アミロイド仮説に基づいて開発が進められてきたADの治療法が臨床試験での成果が得られていないという学術的な問題に対して、アミロイド仮説の前後あるいは並行して起こる超早期のAD分子病態に基づいた治療法の開発を進めることで、我々は問題の解決を目指している。先行研究により同定したAD病態タンパク質の解析を進めることで、認知症のうち最も多いADの予防を含めた治療法の開発が期待できる。本研究の成果は、超高齢化社会を迎えた日本をはじめとし国際的にも高齢化と認知症問題の解決法の一端として社会的に重要な意義がある。

Research Products

• [Journal Article] Ser46-Phosphorylated MARCKS Is a Marker of Neurite Degeneration at the Pre-aggregation Stage in PD/DLB Pathology (2018)
  • Author(s): Fujita Kyota、Homma Hidenori、Kondo Kanoh、Ikuno Masashi、Yamakado Hodaka、Tagawa Kazuhiko、Murayama Shigeo、Takahashi Ryosuke、Okazawa Hitoshi
  • Journal Title: eneuro Volume: 5 Issue: 4 Pages: 0217-18
  • DOI: 10.1523/eneuro.0217-18.2018
  • Peer Reviewed / Open Access
• [Journal Article] The intellectual disability gene PQBP1 rescues Alzheimer’s disease pathology (2018)
  • Author(s): Tanaka Hikari、Kondo Kanoh、Chen Xigui、Homma Hidenori、Tagawa Kazuhiko、Kerever Aurelien、Aoki Shigeki、Saito Takashi、Saido Takaomi、Muramatsu Shin-ichi、Fujita Kyota、Okazawa Hitoshi
  • Journal Title: Molecular Psychiatry Volume: 23 Issue: 10 Pages: 2090-2110
  • DOI: 10.1038/s41380-018-0253-8
  • Peer Reviewed / Open Access
• [Journal Article] Drebrin-like (Dbnl) Controls Neuronal Migration via Regulating N-Cadherin Expression in the Developing Cerebral Cortex (2018)
  • Author(s): Inoue Seika、Hayashi Kanehiro、Fujita Kyota、Tagawa Kazuhiko、Okazawa Hitoshi、Kubo Ken-ichiro、Nakajima Kazunori
  • Journal Title: The Journal of Neuroscience Volume: 39 Issue: 4 Pages: 678-691
  • DOI: 10.1523/jneurosci.1634-18.2018
  • Peer Reviewed / Open Access
• [Journal Article] HMGB1, a pathogenic molecule that induces neurite degeneration via TLR4-MARCKS, is a potential therapeutic target for Alzheimer's disease (2016)
  • Author(s): Fujita, K., Motoki, K., Tagawa, K., Chen, X., Hama, H., Nakajima, K., Homma, H., Tamura, T., Watanabe, H., Katsuno, M., Matsumi, C., Kajikawa, M., Saito, T., Saido, T., Sobue, G., Miyawaki, A., Okazawa, H.
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 31895-31895
  • DOI: 10.1038/srep31895
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Developmental YAPdeltaC determines adult pathology in a mouse model of spinocerebellarataxia type 1. (2018)
  • Author(s): 藤田 慶大、毛 瀅、内田 成則、陳 西貴、塩飽 裕紀、田村 拓也、伊藤 日加瑠、本間 秀典、田川 一彦、岡澤 均
  • Organizer: 日本神経学会
• [Presentation] ハンチントン病における新規ネクローシスTRIADの分子病態（A novel form of necrosis, TRIAD, in Huntington’s disease） (2018)
  • Author(s): 藤田 慶大、Ying Mao、陳 西貴、山西 恵美子、本間 秀典、田川 一彦、岡澤 均
  • Organizer: 日本神経科学会
  • Int'l Joint Research
• [Presentation] Developmental YAPdeltaC determines adult pathology in a model of spinocerebellar ataxia type 1 (2018)
  • Author(s): Kazuhiko Tagawa, Kyota Fujita Ying Mao, Shigenori Uchida, Xigui Chen, Kei Watase, Hidenori Homma, Marius Sudol, Hitoshi Okazawa
  • Organizer: 日本神経科学会
  • Int'l Joint Research
• [Presentation] The hnRNP-Htt axis regulates necrotic cell death induced by transcriptional repression through impaired RNA splicing (2018)
  • Author(s): Hikari Tanaka, Ying Mao, Takuya Tamura, Yoshie Yuki, Daisu Abe, Hidenori Homma,Kazuhiko Tagawa, Hitoshi Okazawa
  • Organizer: 日本神経科学会
  • Int'l Joint Research
• [Presentation] 発生期マウス大脳新皮質深部において、リーリン- DBNLシグナルはNカドヘリン/α-N-カテニンを介して神経細胞移動を制御する」 “Reelin-DBNL signaling regulates neuronal migration via N-cadherin/α -N-catenin complex in the intermediate zone and multipolar cell accumulate zone of the developing mouse cerebral neocortex (2018)
  • Author(s): Seika Inoue, Kanehiro Hayashi, Kyota Fujita, Kazuhiko Tagawa, Hitoshi Okazawa Ken-ichiro Kubo,Kazunori Nakajima
  • Organizer: 日本生物学的精神医学会・日本神経化学会
• [Presentation] アルツハイマー病と前頭側頭葉変性症に共通する異常タウリン酸化とシナプス障害 (2018)
  • Author(s): 藤田慶大、陳西貴、本間秀典、田川一彦、岡澤均、
  • Organizer: 日本認知症学会
• [Presentation] 網羅的リン酸化プロテオーム解析による早期AD病態の解明 (2016)
  • Author(s): 田川 一彦
  • Organizer: 第46回日本神経精神薬理学会年会
  • Place of Presentation: ソウル（韓国）
  • Year and Date: 2016-07-02
  • Int'l Joint Research / Invited