Roles of glial innate immunity in age-related neurodegeneration

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K08637
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: National Center for Geriatrics and Gerontology
• 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)
• Project Period (FY): 2016-04-01 – 2019-03-31
• 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

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.

Free Research Field

神経変性疾患

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。