Creation of novel model mice for dementia research and development of new medicines for dementia treatment.

• Project/Area Number: 24591738
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: HOSOKAWA Masato 公益財団法人東京都医学総合研究所, 認知症・高次脳機能研究分野, 主席研究員 (00435116)
• Co-Investigator(Renkei-kenkyūsha): AKIYAMA Haruhiko 公益財団法人東京都医学総合研究所, 認知症・高次脳機能研究分野, 参事研究員 (20231839)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: 認知症 / TDP-43 / tau / 疾患モデルマウス / タンパク質異常凝集 / グラニュリン / 前頭側頭葉変性症 / プログラニュリン / タウ / アルツハイマー病 / トランスジェニックマウス

Outline of Final Research Achievements

Nobel mice model regarding dementa research were produced for discovering effective drugs. These mice over expressed neurodegenerative diseases associated protein by doxycycline. The abnormal aggregations of these proteins have not observed in neuronal cells yet because aging of mice is not sufficient or other reasons. The results of the other model mice suggest that granulin mutations might contribute to the pathogenesis or be risk factors for tauopathies, including Alzheimer’s disease or corticobasal degeneration.

Research Products

• [Journal Article] Progranulin reduction is associated with tau phosphorylation in P301L tau transgenic mice (2015)
  • Author(s): Hosokawa M, Arai T, Masuda-Suzukake M, Kondo H, Matsuwaki T, Nishihara M, Hasegawa M, Akiyama H
  • Journal Title: J Neuropahol Exp Neurol Volume: 74 Issue: 2 Pages: 158-165
  • DOI: 10.1097/nen.0000000000000158
  • Peer Reviewed
• [Journal Article] Moderate maternal food restriction in mice impairs physical growth, behaviors, and neurodevelopment of offspring (2015)
  • Author(s): Akitake Y, Katsuragi S, Hosokawa M, Mishima K, Ikeda T, Miyazato M, Hosoda H
  • Journal Title: Neutrition Research Volume: 35 Issue: 1 Pages: 76-87
  • DOI: 10.1016/j.nutres.2014.10.014
  • Peer Reviewed
• [Journal Article] An autopsied case of corticobasal degeneration showing severe cerebral atrophy over a protracted disease course of 16 years (2014)
  • Author(s): Kondo D, Hino H, Shibuya K, Fujisawa K, Kosaka K, Hirayasu Y, Yamamoto R, Kasanuki K, Minegishi M, Sato K, Hosokawa M, Arai T, Arai H, Iseki E
  • Journal Title: Neuropathology Volume: Epub ahead of print Issue: 3 Pages: 280-288
  • DOI: 10.1111/neup.12188
  • Peer Reviewed
• [Journal Article] Pathological alpha-synuclein propagates through neural networks (2014)
  • Author(s): Masuda-Suzukake M, Nonaka T, Hosokawa M, Kubo M, Shimozawa A, Akiyama H, Hasegawa M
  • Journal Title: Acta Neuropathol Commun Volume: 2 Issue: 1 Pages: 88-88
  • DOI: 10.1186/preaccept-1296467154135944
  • Peer Reviewed / Open Access
• [Journal Article] Tau accumulation in the nucleus accumbens in tangle-predominant dementia (2014)
  • Author(s): Kawakami I, Hasegawa M, Arai T, Ikeda K, Oshima K, Niizato K, Aoki N, Katsuse O, Higashi S, Hosokawa M, Hirayasu Y, Akiyama H
  • Journal Title: Acta Neuropathol Volume: Commun 2 Issue: 1 Pages: 40-40
  • DOI: 10.1186/2051-5960-2-40
  • Peer Reviewed / Open Access
• [Journal Article] Distinct pathways leading to TDP-43-induced cellular dysfunctions. (2014)
  • Author(s): Yamashita M, Nonaka T, Hirai S, Miwa A, Okado H, Arai T, Hosokawa M, Akiyama H, Hasegawa M.
  • Journal Title: Hum Mol Genet. Volume: 23 Issue: 16 Pages: 4345-56
  • DOI: 10.1093/hmg/ddu152
  • Peer Reviewed / Open Access
• [Journal Article] Differential diagnosis of amyotrophic lateral sclerosis from Guillain-Barré syndrome by quantitative determination of TDP-43 in cerebrospinal fluid. (2014)
  • Author(s): Hosokawa M, Arai T, Yamashita M, Tsuji H, Nonaka T, Masuda-Suzukake M, Tamaoka A, Hasegawa M, Akiyama H.
  • Journal Title: Int. J. Neurosci. Volume: 124 Issue: 5 Pages: 344-349
  • DOI: 10.3109/00207454.2013.848440
  • Peer Reviewed
• [Journal Article] Pathological features of FTLD-FUS in a Japanese population: Analyses of nine cases. (2013)
  • Author(s): Kobayashi Z, Kawakami I, Arai T, Yokota O, Tsuchiya K, Kondo H, Shimomura Y, Haga C, Aoki N, Hasegawa M, Hosokawa M, Oshima K, Niizato K, Ishizu H, Terada S, Onaya M, Ikeda M, Oyanagi K, Nakano I, Murayama S, Akiyama H, Mizusawa H.
  • Journal Title: Neurol. Sci. Volume: 335 Issue: 1-2 Pages: 89-95
  • DOI: 10.1016/j.jns.2013.08.035
  • Peer Reviewed
• [Journal Article] Microsomal prostaglandin E synthase-1 is induced in Alzheimer's disease and its deletion mitigates Alzheimer's disease-like pathology in a mouse model (2013)
  • Author(s): Akitake Y, Nakatani Y, Kamei D, Hosokawa M, Akatsu H, Uematsu S, Akira S, Kudo I, Hara S, Takahashi M
  • Journal Title: J. Neurosci. Res Volume: 91(7) Issue: 7 Pages: 909-919
  • DOI: 10.1002/jnr.23217
  • Peer Reviewed
• [Journal Article] Prion-like spreading of pathological alpha-synuclein in brain. (2013)
  • Author(s): Masuda-Suzukake M, Nonaka T, Hosokawa M., Oikawa T, Arai T, Akiyama H, Mann D, Hasegawa M
  • Journal Title: Brain Volume: 136 Issue: 4 Pages: 1128-38
  • DOI: 10.1093/brain/awt037
  • Peer Reviewed
• [Journal Article] Atypical FTLD-FUS associated with ALS-TDP : a case report (2013)
  • Author(s): Kobayashi Z, Arai T, Yokota O, Tsuchiya K, Hosokawa M, Oshima K, Niizato K, Akiyama H, Mizusawa H
  • Journal Title: Neuropathology Volume: 33 Issue: 1 Pages: 83-86
  • DOI: 10.1111/j.1440-1789.2012.01325.x
  • Peer Reviewed
• [Journal Article] Methylene blue reduced abnormal tau accumulation in P301L tau transgenic mice. (2012)
  • Author(s): Hosokawa M
  • Journal Title: PLoS One Volume: 7 Issue: 12 Pages: e52389-e52389
  • DOI: 10.1371/journal.pone.0052389
  • Peer Reviewed
• [Journal Article] Long-term oral intake of aluminium or zinc does not accelerate Alzheimer pathology in AβPP and AβPP/tau transgenic mice (2012)
  • Author(s): Akiyama H, Hosokawa M, Kametani F, Kondo H, Chiba M, Fukushima M, Tabira T
  • Journal Title: Neuropathology Volume: (in press) Issue: 4 Pages: 390-397
  • DOI: 10.1111/j.1440-1789.2011.01274.x
  • Peer Reviewed
• [Journal Article] Molecular analysis and biochemical classification of TDP-43 proteinopathy (2012)
  • Author(s): Tsuji H
  • Journal Title: Brain Volume: 135(11) Issue: 11 Pages: 3380-91
  • DOI: 10.1093/brain/aws230
  • Peer Reviewed
• [Presentation] プログラニュリンの減少はタウのリン酸化を亢進させる (2014)
  • Author(s): 細川雅人、新井哲明、増田－鈴掛雅美、近藤ひろみ、松脇貴志、西原真杉、長谷川成人、秋山治彦
  • Organizer: 第33回 日本認知症学会
  • Place of Presentation: 横浜 パシフィコ横浜
  • Year and Date: 2014-11-30
• [Presentation] Does frontotemporal dementia associated with chorea suggest the diagnosis of frontotemporal lobar degeneration with fused in sarcoma positive inclusions of the basophilic inclusion body disease subtype? (2014)
  • Author(s): Kawakami I, Kobayashi Z, Arai T, Yokota O, Niizato K, Oshima K, Hosokawa M, Akiyama H
  • Organizer: The 11th International Conference on Alzheimer's & Parkinson's Diseases
  • Place of Presentation: Vancouver, B.C. Canada
  • Year and Date: 2014-10-23 – 2014-10-25
• [Presentation] 妊婦の摂取栄養が子供の脳と精神に及ぼす影響 (2014)
  • Author(s): 秋武義治、桂木真司、細川雅人、池田智明、細田洋司
  • Organizer: 第3回 日本DOHaD研究会学術集会
  • Place of Presentation: 東京 国立成育医療研究センター
  • Year and Date: 2014-07-25
• [Presentation] Analysis of Tau phosphorylation in Tauopathy using Phos-tag SDS-PAGE (2014)
  • Author(s): 木村妙子、細川智永、堤弘次、初田裕幸、鈴掛－増田雅美、細川雅人、福島寛美、石黒幸一、秋山治彦、村山繁雄、長谷川成人、久永眞市
  • Organizer: 第55回 日本神経病理学会
  • Place of Presentation: 東京 学術総合センター
  • Year and Date: 2014-06-07
• [Presentation] タウトランスジェニックマウスにおいてプログラニュリンの減少はタウのリン酸化に影響を与える (2014)
  • Author(s): 細川雅人、新井哲明、増田－鈴掛雅美、近藤ひろみ、松脇貴志、西原真杉、長谷川成人、秋山治彦
  • Organizer: 第61回 日本実験動物学会
  • Place of Presentation: 札幌 札幌コンベンションセンター
  • Year and Date: 2014-05-15
• [Presentation] レビー小体型認知症患者脳不溶性画分の脳内接種は野生型マウス脳にレビー小体様病理を形成させる (2013)
  • Author(s): 鈴掛雅美、野中隆、細川雅人、笈川貴行、新井哲明、秋山治彦、マン デイビッド、長谷川成人
  • Organizer: 第54回 日本神経病理学会
  • Place of Presentation: 東京 タワーホール船堀
• [Presentation] 蓄積αシヌクレインはマウス脳内でプリオン様の伝播能を示す (2013)
  • Author(s): 鈴掛雅美、野中隆、細川雅人、笈川貴行、新井哲明、David M. A. Mann、秋山治彦、長谷川成人
  • Organizer: 第86回 日本生化学会
  • Place of Presentation: 横浜 パシフィコ横浜
• [Presentation] 全経過16年で高度な大脳萎縮を呈した皮質基底核変性症の1剖検例 (2013)
  • Author(s): 近藤大三, 井関栄三, 笠貫浩史, 峯岸道子, 新井平伊, 細川雅人, 新井哲明, 日野博昭, 藤澤浩四郎, 小阪憲司
  • Organizer: 第32回 日本認知症学会
  • Place of Presentation: 松本 キッセイ文化ホール
• [Presentation] アルツハイマー病脳における神経炎症 (2013)
  • Author(s): 秋山治彦, 下村洋子, 近藤ひろみ, 羽賀千恵, 細川雅人
  • Organizer: 第32回 日本認知症学会
  • Place of Presentation: 松本 キッセイ文化ホール
  • Invited
• [Presentation] タウオパチー病理変化の基礎 (2013)
  • Author(s): 新井哲明, 河上緒, 小林禅, 野中隆, 長谷川成人, 細川雅人, 秋山治彦, 池田研二, 朝田隆
  • Organizer: 第32回 日本認知症学会
  • Place of Presentation: 松本 キッセイ文化ホール
  • Invited
• [Presentation] Progranulin reduction affects tau phosphorylation in P301L tau transgenic mice (2013)
  • Author(s): Hosokawa M, Arai T, Masuda-Suzukake M, Nonaka T, Yamashita M, Matsuwaki T, Nishihara M, Hasegawa M, Akiyama H
  • Organizer: The 11th International Conference on Alzheimer's & Parkinson's Diseases
  • Place of Presentation: Florence, Italy
• [Presentation] Methylene blue reduced tau phosphorylation and aggregation in P301L transgenic mice (2012)
  • Author(s): Hosokawa M, Arai T, Nonaka T, Yamashita M, Suzukake M, Hasegawa M, Akiyama H
  • Organizer: Alzheimer's Association International Conference 2012
  • Place of Presentation: Vancouver, BC, Canada
• [Remarks] 公益財団法人東京都医学総合研究所 認知症・高次脳機能研究分野 認知症プロジェクト
  • URL: http://www.igakuken.or.jp/dementia/