Investigating mechanisms of tau-induced neurotxicity

• Project/Area Number: 19K06896
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 46010:Neuroscience-general-related
• Research Institution: National Institutes for Quantum Science and Technology
• Principal Investigator: Sahara Naruhiko 国立研究開発法人量子科学技術研究開発機構, 量子医科学研究所 脳機能イメージング研究部, 上席研究員 (40261185)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: タウ / モデル動物 / 毒性伝播 / 細胞毒性 / タウオパチー / 脳萎縮 / タウ蛋白質 / プリオン様伝播 / 凝集タンパク質伝播 / 生体イメージング / 神経変性疾患 / 動物モデル

Outline of Research at the Start

脳老化に起因する神経変性疾患の多くは、特定タンパク質の機能低下あるいは毒性獲得などに誘発される可能性が指摘されている。申請者は、タウ毒性伝播仮説の検証と毒性制御メカニズムの解明を目指し、生体イメージング技術を用いたタウタンパク質毒性メカニズムの探索とタウオパチーの治療薬開発を進めている。本研究では、タウ毒性伝播メカニズムの解明にむけて、独自のタウ凝集伝播の細胞・動物モデルを構築し、タンパク質凝集過程、細胞死、凝集タンパク質伝播過程などについて生体イメージング技術を用いて検証し、毒性分子種の同定とタウ伝播を抑制しうる治療薬の開発を目指す。

Outline of Final Research Achievements

Neuropathological observations revealed the existence of abundant inclusions with the properties of amyloid fibrils. Most neurodegenerative diseases are defined by multiple types of inclusion consisting of aggregated forms of protein or peptide called proteinopathy. The microtubule-associated protein tau abnormally aggregates into intracellular, filamentous inclusions (NFTs) in brains of individuals with neurodegenerative diseases including Alzheimer’s disease (AD). NFTs are closely associated with the severity of brain function loss in AD. Thus, making tau protein a target in the treatment of AD has become a major therapeutic strategy. Here, we established cellular and mouse models of tauopathy showing cell-cell propagation and pathological tau accumulation. In addition, tauopathy-linked microglial phenotypic change distinct was observed in the mouse model of tauopathy. These models will be essential tools for investigating mechanisms of tau-induced neurotoxicity.

Academic Significance and Societal Importance of the Research Achievements

アルツハイマー病を代表とする多くの認知症では、タウ蛋白質の細胞内沈着を病理学的特徴としたタウオパチーと呼ばれる疾患群が存在し、タウ病態は神経細胞死と密接に関係している。タウ病態の進行を食い止める方法を確立することが、多くの認知症の治療に結びつくと考えられることから、本研究で掲げたタウ毒性制御メカニズムの解明は直近の課題であると言える。

Research Products

• [Journal Article] MRS-measured glutamate versus GABA reflects excitatory versus inhibitory neural activities in awake mice (2022)
  • Author(s): Takado Yuhei、Takuwa Hiroyuki、Sampei Kazuaki、Urushihata Takuya、Takahashi Manami、Shimojo Masafumi、Uchida Shoko、Nitta Nobuhiro、Shibata Sayaka、Nagashima Keisuke、Ochi Yoshihiro、Ono Maiko、Maeda Jun、Tomita Yutaka、Sahara Naruhiko、Near Jamie、Aoki Ichio、Shibata Kazuhisa、Higuchi Makoto
  • Journal Title: J. Cereb. Blood Flow Metab. Volume: 42 Pages: 197-212
  • DOI: 10.1177/0271678x211045449
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Endothelial expression of human amyloid precursor protein leads to amyloid β in the blood and induces cerebral amyloid angiopathy in knock-in mice (2022)
  • Author(s): Tachida Yuriko、Miura Saori、Muto Yui、Takuwa Hiroyuki、Sahara Naruhiko、Shindo Akihiro、Matsuba Yukio、Saito Takashi、Taniguchi Naoyuki、Kawaguchi Yasushi、Tomimoto Hidekazu、Saido Takaomi、Kitazume Shinobu
  • Journal Title: Journal of Biological Chemistry Volume: - Pages: 101880-101880
  • DOI: 10.1016/j.jbc.2022.101880
  • Peer Reviewed / Open Access
• [Journal Article] A genetically targeted reporter for PET imaging of deep neuronal circuits in mammalian brains (2021)
  • Author(s): Shimojo M、Ono M、Takuwa H、Mimura K、Nagai Y、Fujinaga M、Kikuchi T、Okada M、Seki C、Tokunaga M、Maeda J、Takado Y、Takahashi M、Minamihisamatsu T、Zhang M‐R、Tomita Y、Suzuki N、Maximov A、Suhara T、Minamimoto T、Sahara N、Higuchi M
  • Journal Title: EMBO J. Volume: 40
  • DOI: 10.15252/embj.2021107757
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Neurodegenerative processes accelerated by protein malnutrition and decelerated by essential amino acids in a tauopathy mouse model (2021)
  • Author(s): Sato H、Takado Y、Toyoda S、Tsukamoto-Yasui M、Minatohara K、Takuwa H、Urushihata T、Takahashi M、Shimojo M、Ono M、Maeda J、Orihara A、Sahara N、Aoki I、Karakawa S、Isokawa M、Kawasaki N、Kawasaki M、Ueno S、Kanda M、Nishimura M、Suzuki K、Mitsui A、Nagao K、Kitamura A、Higuchi M
  • Journal Title: Science Advances Volume: 7 Pages: 1-11
  • DOI: 10.1126/sciadv.abd5046
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High-Contrast In Vivo Imaging of Tau Pathologies in Alzheimer's and Non-Alzheimer's Disease Tauopathies (2021)
  • Author(s): Tagai K, Ono M, Kubota M, Kitamura S, Takahata K, Seki C, Takado Y, Shinotoh H, Sano Y, Yamamoto Y, Matsuoka K, Takuwa H, Shimojo M, (24人省略), Shimada H.
  • Journal Title: Neuron Volume: 109 Pages: 42-58
  • DOI: 10.1016/j.neuron.2020.09.042
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Microglial gene signature reveals loss of homeostatic microglia associated with neurodegeneration of Alzheimer's disease (2021)
  • Author(s): Sobue A, Kimine O, Hara Y, Endo F, Mizoguchi H, Watanabe S, Murayama S, Saito T, Saido T. C., Sahara N, Higuchi M, Ogi T, Yamanaka K.
  • Journal Title: Acta Neuropathologica Communications Volume: 9 Pages: 1-1
  • DOI: 10.1186/s40478-020-01099-x
  • Peer Reviewed / Open Access
• [Journal Article] Detection of Alzheimer’s disease-related neuroinflammation by a PET ligand selective for glial versus vascular translocator protein (2021)
  • Author(s): Ji Bin、Ono Maiko、Yamasaki Tomoteru、Fujinaga Masayuki、Zhang Ming-Rong、Seki Chie、Aoki Ichio、Kito Seiji、Sawada Makoto、Suhara Tetsuya、Sahara Naruhiko、Higuchi Makoto
  • Journal Title: Journal of Cerebral Blood Flow & Metabolism Volume: - Pages: 1-14
  • DOI: 10.1177/0271678x21992457
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Distinct microglial response against Alzheimer's amyloid and tau pathologies characterized by P2Y12 receptor (2021)
  • Author(s): 93.Maeda J. Sahara N.（他１９名）
  • Journal Title: Brain Communications Volume: 3 Issue: 1 Pages: 1-19
  • DOI: 10.1093/braincomms/fcab011
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cryo-EM structures of tau filaments from Alzheimer’s disease with PET ligand APN-1607 (2021)
  • Author(s): Shi Yang、Murzin Alexey G.、Falcon Benjamin、Epstein Alexander、Machin Jonathan、Tempest Paul、Newell Kathy L.、Vidal Ruben、Garringer Holly J.、Sahara Naruhiko、Higuchi Makoto、Ghetti Bernardino、Jang Ming-Kuei、Scheres Sjors H. W.、Goedert Michel
  • Journal Title: Acta Neuropathologica Volume: 141 Pages: 697-708
  • DOI: 10.1007/s00401-021-02294-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Neuroprotective effect of mitochondrial translocator protein ligand in a mouse model of tauopathy (2021)
  • Author(s): Fairley Lauren H.、Sahara Naruhiko、Aoki Ichio、Ji Bin、Suhara Tetsuya、Higuchi Makoto、Barron Anna M.
  • Journal Title: Journal of Neuroinflammation Volume: 18
  • DOI: 10.1186/s12974-021-02122-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nasal vaccine delivery attenuates brain pathology and cognitive impairment in tauopathy model mice (2020)
  • Author(s): Takeuchi Hiroki、Imamura Keiko、Ji Bin、Tsukita Kayoko、Enami Takako、Takao Keizo、Miyakawa Tsuyoshi、Hasegawa Masato、Sahara Naruhiko、Iwata Nobuhisa、Inoue Makoto、Hara Hideo、Tabira Takeshi、Ono Maiko、Trojanowski John Q.、Lee Virginia M.-Y.、Takahashi Ryosuke、Suhara Tetsuya、Higuchi Makoto、Inoue Haruhisa
  • Journal Title: NPJ Vaccines Volume: 5 Pages: 28-28
  • DOI: 10.1038/s41541-020-0172-y
  • NAID: 120006817588
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Selective Disruption of Inhibitory Synapses Leading to Neuronal Hyperexcitability at an Early Stage of Tau Pathogenesis in a Mouse Model. (2020)
  • Author(s): Shimojo M, Takuwa H, Takado Y, Tokunaga M, Tsukamoto S, Minatohara K, Ono M, Seki C, Maeda J, Urushihata T, Minamihisamatsu T, Aoki I, Kawamura K, Zhang MR, Suhara T, Sahara N, Higuchi M.
  • Journal Title: Journal of Neuroscience Volume: 40 Pages: 3491-3501
  • DOI: 10.1523/jneurosci.2880-19.2020
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] In vivo positron emission tomography imaging of mitochondrial abnormalities in a mouse model of tauopathy (2020)
  • Author(s): Barron Anna M.、Ji Bin、Fujinaga Masayuki、Zhang Ming-Rong、Suhara Tetsuya、Sahara Naruhiko、Aoki Ichio、Tsukada Hideo、Higuchi Makoto
  • Journal Title: Neurobiology of Aging Volume: 94 Pages: 140-148
  • DOI: 10.1016/j.neurobiolaging.2020.05.003
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Pick’s Tau Fibril Shows Multiple Distinct PET Probe Binding Sites: Insights from Computational Modelling (2020)
  • Author(s): Mishra Sushil、Yamaguchi Yoshiki、Higuchi Makoto、Sahara Naruhiko
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Pages: 349-349
  • DOI: 10.3390/ijms22010349
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] In vivo binding of a tau imaging probe, [ 11 C]PBB3, in patients with progressive supranuclear palsy (2019)
  • Author(s): Endo Hironobu、Shimada Hitoshi、Sahara Naruhiko、Ono Maiko、Koga Shunsuke、Kitamura Soichiro、Niwa Fumitoshi、Hirano Shigeki、Kimura Yasuyuki、Ichise Masanori、Shinotoh Hitoshi、Zhang Ming Rong、Kuwabara Satoshi、Dickson Dennis W.、Toda Tatsushi、Suhara Tetsuya、Higuchi Makoto
  • Journal Title: Movement Disorders Volume: 34 Pages: 744-754
  • DOI: 10.1002/mds.27643
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Tau binding protein CAPON induces tau aggregation and neurodegeneration (2019)
  • Author(s): Hashimoto Shoko、Matsuba Yukio、Kamano Naoko、Mihira Naomi、Sahara Naruhiko、Takano Jiro、Muramatsu Shin-ichi、Saido Takaomi C.、Saito Takashi
  • Journal Title: Nature Communications Volume: 10
  • DOI: 10.1038/s41467-019-10278-x
  • Peer Reviewed / Open Access
• [Journal Article] Tau isoform expression and phosphorylation in marmoset brains. (2019)
  • Author(s): Sharma, G., Hisanaga, S., et al.
  • Journal Title: J. Biol. Chem. Volume: 294 Pages: 11433-11444
  • DOI: 10.1074/jbc.ra119.008415
  • Peer Reviewed / Open Access
• [Journal Article] PET-detectable tau pathology correlates with long-term neuropsychiatric outcomes in patients with traumatic brain injury (2019)
  • Author(s): Takahata K、Kimura Yi、Sahara N、Koga S、Shimada H、Ichise M、Saito F、Moriguchi S、Kitamura S、Kubota M、Umeda S、Niwa F、Mizushima J、Morimoto Y、Funayama M、Tabuchi H、Bieniek K. F、Kawamura K、Zhang Ming-Rong、Dickson D. W、Mimura M、Kato M、Suhara T、Higuchi M
  • Journal Title: Brain Volume: 142 Pages: 3265-3279
  • DOI: 10.1093/brain/awz238
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Pathological Progression Induced by the Frontotemporal Dementia-Associated R406W Tau Mutation in Patient-Derived iPSCs (2019)
  • Author(s): Nakamura Mari、Shiozawa Seiji、Tsuboi Daisuke、Amano Mutsuki、Watanabe Hirotaka、Maeda Sumihiro、Kimura Taeko、Yoshimatsu Sho、Kisa Fumihiko、Karch Celeste M.、Miyasaka Tomohiro、Takashima Akihiko、Sahara Naruhiko、Hisanaga Shin-ichi、Ikeuchi Takeshi、Kaibuchi Kozo、Okano Hideyuki
  • Journal Title: Stem Cell Reports Volume: 13 Pages: 684-699
  • DOI: 10.1016/j.stemcr.2019.08.011
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Crosstalk between neurodegeneration and neuroinflammation in mouse models of tauopathy (2021)
  • Author(s): 佐原 成彦
  • Organizer: IUBMB Focused Meeting on Neurodegenerative Diseases, International Union of Biochemistry and Molecular biology
  • Int'l Joint Research / Invited
• [Presentation] 認知症早期診断を目指した生体イメージングバイオマーカーの探索 (2021)
  • Author(s): 佐原 成彦
  • Organizer: 第60回日本生体医工学会大会
  • Invited
• [Presentation] 認知症における恒常性ミクログリア動態 (2021)
  • Author(s): 佐原 成彦
  • Organizer: 第40回日本認知症学会学術集会
  • Invited
• [Presentation] Microglial contributions to neurodegeneration in tauopathy (2020)
  • Author(s): 佐原 成彦
  • Organizer: 第39回日本認知症学会学術集会
  • Invited
• [Presentation] タウオパチーの多様性を考慮した診断・治療薬開発について－現状および今後の展望－ (2020)
  • Author(s): 佐原 成彦
  • Organizer: 第38回日本神経治療学会学術集会
  • Invited
• [Presentation] Microglial contributions to tau-induced neurodegeneration in a mouse model of tauopathy (2020)
  • Author(s): Sahara Naruhiko
  • Organizer: Tau2020
  • Int'l Joint Research
• [Presentation] Dissecting neurofibrillary tangle formation in cellular and mouse models of tauopathy (2019)
  • Author(s): Sahara Naruhiko
  • Organizer: APPS2019
  • Int'l Joint Research
• [Presentation] マルチモーダルイメージングによる認知症発症メカニズムの探索 (2019)
  • Author(s): 佐原 成彦
  • Organizer: 第37回日本神経治療学会学術集会
• [Presentation] 生体イメージング技術を基盤としたタウオパチー創薬プラットフォームの開発 (2019)
  • Author(s): 佐原 成彦
  • Organizer: 第 38 回日本認知症学会学術集会
• [Presentation] Distinct microglial response against Alzheimer’s pathologies characterized by P2Y12 receptor (2019)
  • Author(s): Naruhiko Sahara, Jun Maeda, Takeharu Minamihisamatsu, Masafumi Shimojo, Maiko Ono, Keiichiro Minatohara, Hiroyuki Takuwa, Yuhei Takado, Bin Ji, Ming-Rong Zhang, Makoto Higuchi
  • Organizer: SFN2019
  • Int'l Joint Research