Development and analysis of new Alzheimer's disease model mice which can reproduce age-related changes in brain.

• Project/Area Number: 25290039
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Laboratory animal science
• Research Institution: National Institutes of Biomedical Innovation, Health and Nutrition
• Principal Investigator: Matsuda Junichiro 国立研究開発法人医薬基盤・健康・栄養研究所, 疾患モデル小動物研究室, 研究リーダー (60181731)
• Co-Investigator(Kenkyū-buntansha): KIMURA Nobuyuki 国立研究開発法人国立長寿医療研究センター, 認知症先進医療開発センター・アルツハイマー病研究部・病因遺伝子研究室, 室長 (80392330) ; TAKAHASHI Ichiro 国立研究開発法人医薬基盤・健康・栄養研究所, 霊長類医科学研究センター, 再雇用職員 (90171470)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000); Fiscal Year 2015: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥7,670,000 (Direct Cost: ¥5,900,000、Indirect Cost: ¥1,770,000)
• Keywords: 疾患モデル動物 / アルツハイマー病 / 加齢

Outline of Final Research Achievements

We aimed to develop brand-new Alzheimer’s disease model mice which can reproduce age-related changes such as endocytic pathology. Our previous studies showed that the alteration in dynein-mediated retrograde transport can reproduce age-related endocytic pathology in vitro. Therefore, we tried to generate the transgenic mice which specifically express shRNA against dynein in neuronal cells. Although we confirmed that our shRNA efficiently downregulated dynein in vitro analyses, we failed to observe the knockdown of dynein in the brain of generated mice. We observed neither cognitive dysfunction nor endocytic pathology in the mice. Since we confirmed the strong downregulation of dynein in vitro analyses, we considered that the expression level of shRNA would be insufficient in vivo. Thus, we attempt to use more potent promoters to generate new Alzheimer’s disease model mice in future.

Research Products

• [Journal Article] Dynein Dysfunction Reproduces Age-Dependent Retromer Deficiency: Concomitant Disruption of Retrograde Trafficking Is Required for Alteration in APP Metabolism. (2016)
  • Author(s): Kimura N, Samura E, Suzuki K, Okabayashi S, Shimozawa N, Yasutomi N.
  • Journal Title: Am J Pathol Volume: -
  • Peer Reviewed
• [Journal Article] Retromer and Rab2-dependent trafficking mediate PS1 degradation by proteasomes in endocytic disturbance. (2016)
  • Author(s): Ueda N, Tomita T, Yanagisawa K, Kimura N.
  • Journal Title: J Neurochem Volume: -
  • Peer Reviewed
• [Journal Article] TDP-43 recognizes RNA G-quadruplex structures, and controls neurite mRNA transport for local protein synthesis. (2016)
  • Author(s): Ishiguro A, Kimura N, Watanabe Y, Watanabe S, Ishihama A.
  • Journal Title: Genes Cells Volume: -
  • Peer Reviewed
• [Journal Article] 脳の老年性病態に基づくアルツハイマー病（AD）の発症メカニズム. (2016)
  • Author(s): 木村展之
  • Journal Title: 日本臨牀 Volume: 74 Pages: 378-381
• [Journal Article] エンドサイトーシス障害とアルツハイマー病態：Traffic Jamがもたらす脳神経系への影響. (2015)
  • Author(s): 木村展之
  • Journal Title: Dementia Japan Volume: 29 Pages: 476-485
• [Journal Article] Diabetes mellitus accelerates Aβ pathology in brain accompanied by enhanced GAβ generation in nonhuman primates. (2015)
  • Author(s): Okabayashi S, Shimozawa N, Yasutomi Y, Yanagisawa K, Kimura N.
  • Journal Title: PLoS ONE Volume: 10 Issue: 2 Pages: e0117362-e0117362
  • DOI: 10.1371/journal.pone.0117362
  • Peer Reviewed / Open Access
• [Journal Article] A potential function for neuronal exosomes: sequestering intracerebral amyloid-beta peptide. (2015)
  • Author(s): Yuyama, K., Sun, H., Usuki, S., Sakai, S., Hanamatsu, H., Mioka, T., Kimura, N., Okada, M., Tahara, H., Furukawa, J., Fujitani, N., Shinohara, Y. & Igarashi, Y.
  • Journal Title: FEBS letters Volume: 589 Issue: 1 Pages: 84-88
  • DOI: 10.1016/j.febslet.2014.11.027
  • NAID: 120005537475
  • Peer Reviewed / Open Access
• [Journal Article] Dynein dysfunction disrupts Aβ clearance in astrocytes via endocytic disturbances. (2014)
  • Author(s): Kimura N, Okabayashi S, Ono F.
  • Journal Title: Neuroreport Volume: 25 Issue: 7 Pages: 514-520
  • DOI: 10.1097/wnr.0000000000000124
  • Peer Reviewed
• [Journal Article] Transcriptome analysis of distinct mouse strains reveals kinesin light chain-1 splicing as as amyloid beta accumulation modifier (2014)
  • Author(s): Morihara, T., Hayashi, N., Yokokoji, M., Akatsu, H., Silverman, MA., Kimura, N., Saito, Y., Suzuki, T., Yanagida, K., Tanaka, T., Kazui, H., Kudo, T., Kodama, TS., Sato, M., Hashimoto, R., Tagami, S., Okochi, M., Ytoh, N., Nishitomi, K., Takamura, H., Katayama, T., Hashizumi, Y., Kimura, R., Kamino, K., Takeda, M
  • Journal Title: Proc. Acad. Natl. Sci. USA Volume: 111 Issue: 7 Pages: 2638-2643
  • DOI: 10.1073/pnas.1307345111
  • Peer Reviewed / Open Access
• [Presentation] The perturbation of intracellular presenilin 1 transport aggravated β-amyloidogenesis in endosomes. (2016)
  • Author(s): Ueda N, Tomita T, Yanagisawa K, Kimura N.
  • Organizer: 第8回NAGOYAグローバルリトリート
  • Place of Presentation: 大府市
  • Year and Date: 2016-02-12
  • Int'l Joint Research
• [Presentation] Type II diabetes mellitus enhances GAβ generation and accelerates Aβ pathology in nonhuman primate brain. (2016)
  • Author(s): Kimura N.
  • Organizer: 11th Internatinal Symposium on Geriatrics and Gerontology
  • Place of Presentation: 大府市
  • Year and Date: 2016-02-06
  • Int'l Joint Research
• [Presentation] 老化に伴う細胞内輸送機能の障害とアルツハイマー病態 (2015)
  • Author(s): 木村展之
  • Organizer: BMB2015（第88回日本生化学会）
  • Place of Presentation: 神戸市
  • Year and Date: 2015-12-01
• [Presentation] プレセニリン1の細胞内局在におけるレトロマーの関与. (2015)
  • Author(s): 上田直也, 富田泰輔, 柳澤勝彦, 木村展之.
  • Organizer: BMB2015（第88回日本生化学会）
  • Place of Presentation: 神戸市
  • Year and Date: 2015-12-01
• [Presentation] エンドサイトーシス障害とPresenilin-1：retromerとERADによる共役機構. (2015)
  • Author(s): 木村展之, 上田直也, 富田泰輔, 柳澤勝彦.
  • Organizer: 第34回日本認知症学会
  • Place of Presentation: 青森市
  • Year and Date: 2015-10-02
• [Presentation] Endocytic pathology in astrocytes: dynein dysfunction disrupts Abeta clearance in astrocytes via disturbed endosome trafficking. (2015)
  • Author(s): Kimura N, Okabayashi S, Ono F.
  • Organizer: 第58回日本神経化学会
  • Place of Presentation: 大宮市
  • Year and Date: 2015-09-11
• [Presentation] The dysfunction of retrograde transport is sufficient to disrupt Abeta clearance in astrocytes via disturbed endosome trafficking. (2015)
  • Author(s): Kimura N, Okabayashi S, Ono F.
  • Organizer: 40th Congress of the Federation of the European Biochemical Societies (FEBS)
  • Place of Presentation: ベルリン
  • Year and Date: 2015-07-04
  • Int'l Joint Research
• [Presentation] Ⅱ型糖尿病は老年性エンドサイトーシス障害の増悪を介してAβ病理を加速化する. (2015)
  • Author(s): 木村展之, 岡林佐知, 下澤律浩, 保富康宏, 柳澤勝彦
  • Organizer: 第38回日本基礎老化学会
  • Place of Presentation: 横浜市
  • Year and Date: 2015-06-12
• [Presentation] ENDOCYTIC DISTURBANCE DISRUPTS ABETA CLEARANCE IN ASTROCYTES WITHOUT AFFECTING ABETA UPTAKE. (2015)
  • Author(s): Kimura N, Okabayashi S, Ono F.
  • Organizer: ADPD
  • Place of Presentation: Nice, France
  • Year and Date: 2015-03-18 – 2015-03-22
• [Presentation] The relationship between age-ependent endocytic disturbance and Presenilin-1. (2015)
  • Author(s): Ueda N, Yanagisawa K, Kimura N.
  • Organizer: ADPD
  • Place of Presentation: Nice, France
  • Year and Date: 2015-03-18 – 2015-03-22
• [Presentation] Effects of endocytic disturbance in PS1 localization and γ-secretase complex formation. (2015)
  • Author(s): Ueda N, Yanagisawa K, Kimura N.
  • Organizer: 第7回NAGOYAグローバルリトリート
  • Place of Presentation: 愛知県大府市
  • Year and Date: 2015-02-13 – 2015-02-14
• [Presentation] アルツハイマー病におけるエンドサイトーシス障害：病態解明と創薬標的としての可能性 (2015)
  • Author(s): 木村展之
  • Organizer: シンポジウム「アルツハイマー病先制治療薬の創出」
  • Place of Presentation: 愛知県名古屋市
  • Year and Date: 2015-01-17
  • Invited
• [Presentation] Traffic Jam仮説：老年性エンドサイトーシス障害とアルツハイマー病態との関係. (2014)
  • Author(s): 木村展之
  • Organizer: 第33回日本認知症学会
  • Place of Presentation: 神奈川県横浜市
  • Year and Date: 2014-11-29 – 2014-12-01
  • Invited
• [Presentation] 糖尿病はGM1ガングリオシド結合型 Aβの産生増加を介してAβ病理を加速する. (2014)
  • Author(s): 木村展之, 岡林佐知, 下澤律浩, 保富康宏, 柳澤勝彦.
  • Organizer: 第57回日本神経化学会
  • Place of Presentation: 奈良県奈良市
  • Year and Date: 2014-09-29 – 2014-10-01
• [Presentation] DYNEIN DYSFUNCTION PERTURBS INTRACELLULAR VESICLE TRAFFICKING AND SYNAPTIC VESICLE DOCKING VIA ENDOCYTIC DISTURBANCES: A POTENTIAL MECHANISM UNDERLYING AGE-DEPENDENT COGNITIVE DYSFUNCTION. (2014)
  • Author(s): Kimura N, Okabayashi S, Ono F.
  • Organizer: FENS 2014
  • Place of Presentation: Milan, Italy
  • Year and Date: 2014-07-05 – 2014-07-09
• [Presentation] Dynein dysfunction disrupts synaptic vesicle transport and docking via endocytic disturbance. (2014)
  • Author(s): Kimura N, Okabayashi S, Ono F.
  • Organizer: 第37回日本基礎老化学会
  • Place of Presentation: 愛知県大府市
  • Year and Date: 2014-06-26 – 2014-06-27
• [Presentation] 老化に伴う細胞内輸送機能の障害とアルツハイマー病態 (2014)
  • Author(s): 木村展之
  • Organizer: 第４７回知覚コロキウム
  • Place of Presentation: 愛知県大府市
  • Invited
• [Presentation] Traffic Jam hypothesis: endocytic dysfunction as a risk factor for Alzheimer’s disease pathology. (2014)
  • Author(s): Nobuyuki Kimura
  • Organizer: 第６回NAGOYAグローバルリトリート
  • Place of Presentation: 愛知県大府市
• [Presentation] Endocytic dysfunction in astrocytes of aged cynomolgus monkey brains. (2013)
  • Author(s): Kimura N, Okabayashi S, Ono F.
  • Organizer: Neuro2013（第５６回日本神経化学会）
  • Place of Presentation: 京都市
• [Presentation] Retromerの加齢性局在変化とDynein機能障害との関係 (2013)
  • Author(s): 木村展之、岡林佐知、小野文子、上田直也、下澤律浩、保富康宏、柳澤勝彦
  • Organizer: 第３２回日本認知症学会
  • Place of Presentation: 松本市