Mechanism for the propagation and clearance of tau and alpha-synuclein proteins in neurodegenerative disease
| Project/Area Number |
18K06542
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 46030:Function of nervous system-related
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| Research Institution | National Institutes for Quantum and Radiological Science and Technology |
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Principal Investigator |
Takuwa Hiroyuki 国立研究開発法人量子科学技術研究開発機構, 放射線医学総合研究所 脳機能イメージング研究部, 研究員(任常) (40508347)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2018: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
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| Keywords | タウ / 神経変性疾患 / クリアランス / ミクログリア / 神経細胞 / 二光子顕微鏡 / PET / 2光子顕微鏡 / マクロファージ / 脳内クリアランス / 認知症 / モデルマウス / in vivoイメージング / αシヌクレイン / 脳内伝播 |
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| Outline of Final Research Achievements |
To better understand the mechanism of intracerebral accumulation and clearance of pathogenic proteins that cause neurodegenerative diseases, we performed in vivo brain imaging of disease model animals. We developed an experimental system for visualizing tau and α-synuclein at micrometer resolution using a two-photon microscope, and succeeded in longitudinally observing the accumulation of these pathogenic proteins in neurons. Moreover, we have longitudinally tracked neurons, microglia and aggregated tau with two-photon imaging. Neurons bearing tau fibrils underwent primary phagocytosis by activated microglia, followed by the transport of vesicles containing the neuronal fragments to the brain surface through vertical processes of the microglial cells. We observed that the microglia eventually released the neuronal fragments into the cerebrospinal fluid. Our findings indicate a newly microglial pathway for the clearance of misfolded proteins and neurons from the brain.
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| Academic Significance and Societal Importance of the Research Achievements |
認知症は、病態進行とともに多くの医療費と介護を必要とし、患者本人にも社会的にも負荷が大きい疾患であり、一刻も早い治療法の開発が期待されている。本研究では、神経変性疾患発症の引き金となる病原性蛋白質の脳内蓄積および脳外排出メカニズムの一端を明らかにした。これらの病態メカニズムを基盤として、現在、病原性タンパクの蓄積・排出制御の実現のための研究を進めている。このような生体本来の機能を利用した治療法は、介入に伴う副次的な身体への負荷が小さくしながら、病気の原因を完全に除去することで大きな治療効果を生み出すことが期待される。
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Report
(4 results)
Research Products
(18 results)
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[Journal Article] High-Contrast In Vivo Imaging of Tau Pathologies in Alzheimer’s and Non-Alzheimer’s Disease Tauopathies2021
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.
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Journal Title
Neuron
Volume: 109
Issue: 1
Pages: 42-58
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[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.
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Journal Title
J Neurosci.
Volume: 40
Issue: 17
Pages: 3491-3501
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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