Roles of glial innate immunity in age-related neurodegeneration
| Project/Area Number |
16K08637
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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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| Research Field |
Pathological medical chemistry
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| Research Institution | National Center for Geriatrics and Gerontology |
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Principal Investigator |
IIJIMA Koichi 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, 部長 (50632535)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | アルツハイマー病 / 神経変性疾患 / 加齢 / 自然免疫 / Toll様受容体 / グリア細胞 / ショウジョウバエ / 神経変性 / タウ / 老化 / グリア |
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| Outline of Final Research Achievements |
Toll-like receptors (TLRs) are evolutionally conserved pattern recognition receptors that play central roles in innate immunity. Recent evidence suggests that dysregulation of TLRs are involved in a number of neurodegenerative diseases, including Alzheimer’s diseases. We utilized Drosophila to investigate roles of TLRs in neurodegeneration. We found that among 9 TLRs, mRNA expression levels of Toll-9 were increased during aging, and overexpression of Toll-9 in adult retina induced age-dependent neurodegeneration. We further demonstrated that Toll-9 expression was increased in fly model of tauopathy, and knockdown of Toll-9 suppressed tau-mediated neurodegeneration. These results suggest that induction of Toll-9 is involved in neurodegeneration in flies. We also found that knockdown of Tl/Toll, 18w/Toll-2, and Toll-6 in glial cells caused age-dependent locomotor defects and neurodegeneration. These results suggest that some of TLRs play neuroprotective roles in flies.
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| Academic Significance and Societal Importance of the Research Achievements |
多くの加齢依存性神経変性疾患において、脳内での炎症反応の慢性的亢進が病態の進行と密接に関連すると考えられ、グリア細胞における免疫シグナルが治療薬標的として注目されている。Toll様受容体は自然免疫において重要な役割を担うが、その変化が神経変性へ及ぼす影響は明らかでない。本研究の結果から、ヒトのToll様受容体と最も相同性が高いToll-9の活性化が、加齢、またはタウにより惹起される神経変性を促進することが示された。一方で、一部のToll様受容体は神経保護的作用を有する可能性も分かり、Toll様受容体がアルツハイマー病等の神経変性疾患の発症機序の理解から治療法の開発につながる可能性が示された。
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Report
(4 results)
Research Products
(33 results)
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[Presentation] Ectopic expression of human TREM2/TYROBP in Drosophila glial cells negatively affects transcriptional programs induced by Aβ42 and worsens tau-mediated neurodegeneration.2017
Author(s)
Sekiya, M., Wang, M., Fujisaki, N., Sakakibara, Y., Ehrlich, M.E., Schadt, E.E., Gandy, S., Ando, K., Zhang, B. & Iijima, K.M.
Organizer
AD/PD2017
Related Report
Int'l Joint Research
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[Presentation] CaMKII enhances tau-mediated neurodegeneration downstream of tau phosphorylation in transgenic Drosophila models of tauopathy.2017
Author(s)
Ando, K., Oka, M., Maruko-Otake, A., Ohtake, Y., Sekiya, M., Hisanaga, S., Iijima, K.M.
Organizer
The 4th Asia-Pacific Drosophila Research Conference
Related Report
Int'l Joint Research
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[Presentation] S6 kinase and insulin/IGF signaling regulates accumulation and toxicity of tau through Ser262 phosphorylation in a Drosophila model of tauopathy.2017
Author(s)
Ando, K., Hayashishita, M., Chiku, T., Saito, T., Asada, A., Hisanaga, S., and Iijima K.M.
Organizer
第60回日本神経化学会
Related Report
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[Presentation] システム生物学によるAβ，tau，TREM2/TYROBPの遺伝子相互作用解析2017
Author(s)
Sekiya, M., Wang, M., Fujisaki, N., Sakakibara, Y., Zhang, B. & Iijima, K.M.
Organizer
第36回日本認知症学会学術集会
Related Report
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[Presentation] Protective roles of SUR, a fly homologue of Sulfonylurea receptors, ABCC8/SUR1 and ABCC9/SUR2, against age-associated neurodegenration in Drosophila2017
Author(s)
Quan, X., Fujisaki, N., Sakakibara, Y., Sekiya, M. & Iijima, K.M.
Organizer
第40回日本分子生物学会年会
Related Report
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[Presentation] Suatained activation of CaMKII caused by depletion of mitochondria from the axons enhances tau toxicity2016
Author(s)
Ando, K., Maruko-Otake, A., Hayashishita, M., Oka, M., Ohtake, Y., Sekiya, M., Saito, T., Hisanaga, S.I. & Iijima, K.M.
Organizer
Neuroscience 2016
Place of Presentation
San Diego
Related Report
Int'l Joint Research
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