Development of next-generation therapy based on comprehensive molecular pathology of neurodegenerative diseases

• Project/Area Number: 17H04196
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Okayama University
• Principal Investigator: Abe Koji 岡山大学, 医歯薬学総合研究科, 教授 (20212540)
• Co-Investigator(Kenkyū-buntansha): 太田 康之 岡山大学, 大学病院, 講師 (20746854) ; 山下 徹 岡山大学, 医歯薬学総合研究科, 講師 (60644408)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000); Fiscal Year 2019: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2018: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2017: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: 神経変性疾患 / ALS / アルツハイマー型認知症 / フリーラジカル / 酸化ストレス / 核細胞質輸送障害

Outline of Final Research Achievements

By using a AD model mouse with cerebral blood flow hypoperfusion established recently revealed that edaravone treatment can significantly improve motor and cognitive dysfunction. We also established novel ALS mice model that visualize oxidative stress, and found that the expression of oxidative stress in the spinal cord and lower limb muscles was enhanced early in the onset of ALS. Blood flow and glucose metabolism in the spinal cord of ALS patients were evaluated by PET examination, and it was observed that glucose metabolism was abnormally elevated in the ALS cervical spinal cord without increase in blood flow. Furthermore, as a result of exploratory research using a new peptideme analysis technology, 4 types of peptides specific to mild cognitive impairment (MCI) and Alzheimer's disease (AD) were found.

Academic Significance and Societal Importance of the Research Achievements

本研究は、神経変性疾患共通（普遍性のある）の分子病態解明のため、酸化ストレスと核細胞質輸送障害、蛋白ゲル化異常の相互関与に注目した挑戦的かつ総合的研究である。課題申請者らが発見したAsidanの病態も、欧米で特に多いC9orf72遺伝子異常との類似点から、神経変性疾患共通病態への関与に注目し解明を目指しており、本研究成果は国際的にも重要なインパクトを与えうる。本研究では神経変性疾患共通の分子病態解明および新規治療法開発につながる可能性があり、この課題研究から得られた成果は、将来的には神経変性疾患共通の根本的治療法の確立に道を開き、国際的にも波及効果の高い貢献をもたらすものと考えられる。

Research Products

• [Journal Article] A New Serum Biomarker Set to Detect Mild Cognitive Impairment and Alzheimer's Disease by Peptidome Technology. (2020)
  • Author(s): Abe K, Shang J, Shi X, Yamashita T, Hishikawa N, Takemoto M, Morihara R, Nakano Y, Ohta Y, Deguchi K, Ikeda M, Ikeda Y, Okamoto K, Shoji M, Takatama M, Kojo M, Kuroda T, Ono K, Kimura N, Matsubara E, Osakada Y, Wakutani Y, Takao Y, Higashi Y, Asada K, Senga T, Lee LJ, Tanaka K
  • Journal Title: Journal of Alzheimer's Disease Volume: 73(1) Pages: 217-227
  • DOI: 10.3233/jad-191016
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical and Pathological Benefits of Edaravone for Alzheimer’s Disease with Chronic Cerebral Hypoperfusion in a Novel Mouse Model (2019)
  • Author(s): Feng Tian、Yamashita Toru、Shang Jingwei、Shi Xiaowen、Nakano Yumiko、Morihara Ryuta、Tsunoda Keiichiro、Nomura Emi、Sasaki Ryo、Tadokoro Koh、Matsumoto Namiko、Hishikawa Nozomi、Ohta Yasuyuki、Abe Koji
  • Journal Title: Journal of Alzheimer's Disease Volume: 71 Pages: 327-339
  • DOI: 10.3233/jad-190369
  • Peer Reviewed / Open Access
• [Journal Article] Imaging Hypoxic Stress and the Treatment of Amyotrophic Lateral Sclerosis with Dimethyloxalylglycine in a Mice Model (2019)
  • Author(s): Nomura Emi、Ohta Yasuyuki、Tadokoro Koh、Shang Jingwei、Feng Tian、Liu Xia、Shi Xiaowen、Matsumoto Namiko、Sasaki Ryo、Tsunoda Keiichiro、Sato Kota、Takemoto Mami、Hishikawa Nozomi、Yamashita Toru、Kuchimaru Takahiro、Kizaka-Kondoh Shinae、Abe Koji
  • Journal Title: Neuroscience Volume: 415 Pages: 31-43
  • DOI: 10.1016/j.neuroscience.2019.06.025
  • Peer Reviewed
• [Journal Article] Twendee X Ameliorates Phosphorylated Tau, α-Synuclein and Neurovascular Dysfunction in Alzheimer's Disease Transgenic Mice With Chronic Cerebral Hypoperfusion (2019)
  • Author(s): Liu Xia、Yamashita Toru、Shang Jingwei、Shi Xiaowen、Morihara Ryuta、Huang Yong、Sato Kota、Takemoto Mami、Hishikawa Nozomi、Ohta Yasuyuki、Abe Koji
  • Journal Title: Journal of Stroke and Cerebrovascular Diseases Volume: 28 Pages: 104310-104310
  • DOI: 10.1016/j.jstrokecerebrovasdis.2019.104310
  • Peer Reviewed
• [Journal Article] Chronic cerebral hypoperfusion alters amyloid-β transport related proteins in the cortical blood vessels of Alzheimer’s disease model mouse (2019)
  • Author(s): Shang Jingwei、Yamashita Toru、Tian Feng、Li Xianghong、Liu Xia、Shi Xiaowen、Nakano Yumiko、Tsunoda Keiichiro、Nomura Emi、Sasaki Ryo、Tadokoro Koh、Sato Kota、Takemoto Mami、Hishikawa Nozomi、Ohta Yasuyuki、Abe Koji
  • Journal Title: Brain Research Volume: 1723 Pages: 146379-146379
  • DOI: 10.1016/j.brainres.2019.146379
  • Peer Reviewed
• [Journal Article] Chronic Cerebral Hypoperfusion Activates the Coagulation and Complement Cascades in Alzheimer's Disease Mice (2019)
  • Author(s): Shi Xiaowen、Ohta Yasuyuki、Liu Xia、Shang Jingwei、Morihara Ryuta、Nakano Yumiko、Feng Tian、Huang Yong、Sato Kota、Takemoto Mami、Hishikawa Nozomi、Yamashita Toru、Abe Koji
  • Journal Title: Neuroscience Volume: 416 Pages: 126-136
  • DOI: 10.1016/j.neuroscience.2019.07.050
  • Peer Reviewed
• [Journal Article] Acute Anti-Inflammatory Markers ITIH4 and AHSG in Mice Brain of a Novel Alzheimer’s Disease Model (2019)
  • Author(s): Shi Xiaowen、Ohta Yasuyuki、Liu Xia、Shang Jingwei、Morihara Ryuta、Nakano Yumiko、Feng Tian、Huang Yong、Sato Kota、Takemoto Mami、Hishikawa Nozomi、Yamashita Toru、Abe Koji
  • Journal Title: Journal of Alzheimer's Disease Volume: 68 Pages: 1667-1675
  • DOI: 10.3233/jad-181218
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Benefits of Antioxidative Supplement Twendee X for Mild Cognitive Impairment: A Multicenter, Randomized, Double-Blind, and Placebo-Controlled Prospective Interventional Study (2019)
  • Author(s): Tadokoro Koh、Morihara Ryuta、Abe Koji et al.,
  • Journal Title: Journal of Alzheimer's Disease Volume: 71 Pages: 1063-1069
  • DOI: 10.3233/jad-190644
  • Peer Reviewed / Open Access
• [Journal Article] Enhanced oxidative stress and the treatment by edaravone in mice model of amyotrophic lateral sclerosis (2019)
  • Author(s): Ohta Y, Nomura E, Shang J, Feng T, Huang Y, Liu X, Shi X, Nakano Y, Hishikawa N, Sato K, Takemoto M, Yamashita T, Abe K.
  • Journal Title: J Neurosci Res. Volume: epub ahead of pring Pages: 607-619
  • DOI: 10.1002/jnr.24368
  • Peer Reviewed
• [Journal Article] Detecting spinal pyramidal tract of amyotrophic lateral sclerosis patients with diffusion tensor tractography (2018)
  • Author(s): Fukui Y, Hishikawa N, Sato K, Nakano Y, Morihara R, Shang J, Takemoto M, Ohta Y, Yamashita T, Abe K.
  • Journal Title: Neurosci Res Volume: Epub ahead of print Pages: 58-63
  • DOI: 10.1016/j.neures.2017.11.005
  • Peer Reviewed
• [Journal Article] Flow-metabolism uncoupling in the cervical spinal cord of ALS patients. (2017)
  • Author(s): Yamashita T, Hatakeyama T, Sato K, Fukui Y, Hishikawa N, Ohta Y, Nishiyama Y, Kawai N, Tamiya T, Abe K.
  • Journal Title: Neurol Sci. Volume: 38 Pages: 659-665
  • DOI: 10.1007/s10072-017-2823-y
  • Peer Reviewed
• [Journal Article] Potential multisystem degeneration in Asidan patients. (2017)
  • Author(s): Ohta Y, Yamashita T, Hishikawa N, Sato K, Matsuzono K, Tsunoda K, Hatanaka N, Takemoto M, Takemi T, Takamatsu K, Abe K
  • Journal Title: J Neurol Sci. Volume: 373 Pages: 216-222
  • DOI: 10.1016/j.jns.2017.01.003
  • Peer Reviewed
• [Journal Article] Behavioral and affective features of amyotrophic lateral sclerosis patients. (2017)
  • Author(s): Ohta Y, Sato K, Takemoto M, Takahashi Y, Morihara R, Nakano Y, Tsunoda K, Nomura E, Hishikawa N, Yamashita T, Abe K
  • Journal Title: J Neurol Sci. Volume: 381 Pages: 119-125
  • DOI: 10.1016/j.jns.2017.08.024
  • Peer Reviewed
• [Journal Article] Aberrant distributions of nuclear pore complex proteins in ALS mice and ALS patients. (2017)
  • Author(s): Shang J, Yamashita T, Nakano Y, Morihara R, Li X, Feng T, Liu X, Huang Y, Fukui Y, Hishikawa N, Ohta Y, Abe K
  • Journal Title: Neuroscience. Volume: 350 Pages: 158-168
  • DOI: 10.1016/j.neuroscience.2017.03.024
  • Peer Reviewed
• [Presentation] Therapeutic benefits of edaravone for enhanced oxidative stress in mice model of amyotrophic lateral sclerosis. (2019)
  • Author(s): Ohta Y, Nomura E, Shang J, Feng T, Liu X, Shi X, Hishikawa N, Takemoto M, Yamashita T, Abe K
  • Organizer: BRAIN & BRAIN PET 2019
  • Int'l Joint Research
• [Presentation] Reduction of intracerebral hemorrhage by rivaroxaban after tPA thrombolysis is associated with downregulation of PAR-1 and PAR-2 (2019)
  • Author(s): Yamashita T, Morihara R, Kono S, Shang J, Nakano Y, Sato K, Hishikawa N, Ohta Y, Heitmeier S, Perzborn E, Abe K
  • Organizer: BRAIN & BRAIN PET 2019
  • Int'l Joint Research
• [Presentation] In vivo direct reprogramming of glial linage to mature neurons after cerebral ischemia (2019)
  • Author(s): Yamashita T, Shang J, Nakano Y, Morihara R, Sato K, Takemoto M, Hishikawa N, Ohta Y, Abe K
  • Organizer: Asia Pacific Stroke Conference 2019
  • Int'l Joint Research
• [Presentation] Animal models of vascular cognitive impairment (2019)
  • Author(s): Yamashita T, Abe K
  • Organizer: Asia Pacific Stroke Conference 2019
  • Int'l Joint Research
• [Presentation] Therapeutic effects of edaravone for enhanced oxidative stress in amyotrophic lateral sclerosis mice (2019)
  • Author(s): Ohta Y, Nomura E, Shang J, Feng T, Nakano Y, Hishikawa N, Sato K, Takemoto M, Yamashita T, Omote Y, Abe K
  • Organizer: 第60回日本神経学会学術大会
• [Presentation] ALS幹細胞治療の新展開 (2019)
  • Author(s): 山下徹、阿部康二
  • Organizer: 第60回日本神経学会学術大会
  • Invited
• [Presentation] パーキンソン病とレビー小体型認知症の検査所見やmicrobleeds出現頻度の違いについて (2019)
  • Author(s): 武本麻美、佐藤恒太、太田康之、山下徹、菱川望、阿部康二
  • Organizer: 第60回日本神経学会学術大会
• [Presentation] 新規遺伝性疾患 Asidan (SCA36)におけるDAT scanの特徴 (2019)
  • Author(s): 太田康之、山下徹、菱川望、佐藤恒太、角田慶一郎、幡中典子、武本麻美、商敬偉、阿部康二
  • Organizer: 第42回日本脳神経CI学会総会
• [Presentation] MRI・DAT SPECTでパーキンソニズムの左右差に合致した異常所見を認めた日本脳炎の一例 (2019)
  • Author(s): 田所功、太田康之、佐藤恒太、前木孝洋、武本麻美、菱川望、山下徹、田島茂、林昌宏、阿部康二
  • Organizer: 第42回日本脳神経CI学会総会
• [Presentation] 新規酸化ストレスイメージングによるALSへのエダラボン治療効果の検討 (2019)
  • Author(s): 太田康之、野村恵美、山下徹、馮田、佐藤恒太、武本麻美、菱川望、表芳夫、阿部康二
  • Organizer: 第37回日本神経治療学会
• [Presentation] Clinical predictors of Alzheimer’s disease progression (2019)
  • Author(s): Hishikawa N, Omote Y, Shang J, Takemoto M, Yamashita T, Ohta Y, Abe K
  • Organizer: 第38回 日本認知症学会学術集会
• [Presentation] 細胞移植による神経再生療法 (2019)
  • Author(s): 山下徹、阿部康二
  • Organizer: 第10回日本脳血管・認知症学会総会（Vas-Cog Japan 2019）
  • Invited
• [Presentation] Flow-metabolism uncoupling in the cervical spinal cord of ALS patients. (2018)
  • Author(s): Yamashita T, Nakano Y, Morihara R, Shang J, Sato K, Hishikawa N, Ohta Y, Abe K
  • Organizer: The 11th Pan Pacific Symposium on Stem Cells and Cancer Research
  • Int'l Joint Research
• [Presentation] Clinical features of Asidan patients with DWEP. (2018)
  • Author(s): Ohta Y, Yamashita T, Hishikawa N, Sato K, Tsunoda K, Hatanaka N, Takemoto M, Abe K
  • Organizer: The 2nd Asidan/SCA36 international symposium
  • Int'l Joint Research
• [Presentation] Clinical characterization of Asidan in Japan. (2018)
  • Author(s): Yamashita T, Ohta Y, Abe K
  • Organizer: The 2nd Asidan/SCA36 international symposium
  • Int'l Joint Research
• [Presentation] The pathological role of P413L variant chromogranin B as disease modifier in female amyotrophic lateral sclerosis. (2018)
  • Author(s): Ohta Y, Soucy G, Phaneuf D, Audet JN, Gros-Louis F, Yamashita T, Sato K, Takemoto M, Hishikawa N, Julien JP, Abe K
  • Organizer: 第59回日本神経学会学術大会
• [Presentation] ALSモデルマウス骨格筋における酸化ストレスの関与 (2018)
  • Author(s): 太田康之、野村恵美、商敬偉、山下徹、馮田、黄永、佐藤恒太、武本麻美、菱川望、阿部康二
  • Organizer: 日本筋学会第4回学術集会
• [Presentation] Chronic Cerebral Hypoperfusion Accelerates Alzheimer’s Disease Pathology with Cerebrovascular Remodeling in a Novel Mouse Model (2017)
  • Author(s): Yamashita T, Zhai Y, Nakano Y, Morihara R, Shang J, Abe K
  • Organizer: BRAIN 2017
  • Int'l Joint Research
• [Presentation] ALS患者頚髄では糖代謝と血流のuncouplingが起きている (2017)
  • Author(s): 山下徹、畠山哲宗、佐藤恒太、中野由美子、森原隆太、商敬偉、福井祐介、菱川望、太田康之、西山佳宏、河井信行、田宮隆、阿部康二
  • Organizer: 第60回日本脳循環代謝学会学術集会
• [Presentation] The role of variant chromogranin B as disease modifier in Japanese female amyotrophic lateral sclerosis. (2017)
  • Author(s): Ohta Y, Soucy G, Phaneuf D, Audet JN, Gros-Louis F, Yamashita T, Sato K, Takemoto M, Hishikawa N, Julien JP, Abe K
  • Organizer: XXIII World Congress of Neurology
  • Int'l Joint Research
• [Presentation] 虚血負荷によるTDP43、FUS/TLSの発現亢進と神経細胞保護効果の関係 (2017)
  • Author(s): 中野由美子、孫淼、山下徹、森原隆太、佐藤恒太、菱川望、太田康之、阿部康二
  • Organizer: 第17回日本抗加齢医学会総会
• [Presentation] 新しいSCA/ALS crossroad mutation AsidanのDWEP現象 (2017)
  • Author(s): 太田康之、山下徹、佐藤恒太、幡中典子、角田慶一郎、武本麻美、菱川望、阿部康二
  • Organizer: 第5回日本難病医療ネットワーク学会学術集会
• [Remarks] 少量の血液から認知症リスクが診断可能に！認知症リスクの指標となる血中ペプチドバイオマーカーを発見
  • URL: https://www.okayama-u.ac.jp/tp/release/release_id699.html