| Project/Area Number |
16380195
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Basic veterinary science/Basic zootechnical science
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| Research Institution | Obihiro University of Agriculture and Veterinary Medicine |
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Principal Investigator |
ISHII Toshiaki Obihiro University of Agriculture and Beterianary Medicine, Department of Pathobiological Science, 畜産学部, 助教授 (50264809)
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| Co-Investigator(Kenkyū-buntansha) |
MIYAZAWA Takayuki Kyoto University, Institute for Virus Research, ウイルス研究所, 助教授 (80282705)
FURUOKA Hidefumi Obihiro University of Agriculture and Beterianary Medicine, Department of Pathobiological Science, 畜産学部, 教授 (60238665)
NISHIMURA Masakazu Obihiro University of Agriculture and Beterianary Medicine, Department of Pathobiological Science, 畜産学部, 教授 (50011995)
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| Project Period (FY) |
2004 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥15,500,000 (Direct Cost: ¥15,500,000)
Fiscal Year 2006: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 2005: ¥5,600,000 (Direct Cost: ¥5,600,000)
Fiscal Year 2004: ¥8,000,000 (Direct Cost: ¥8,000,000)
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| Keywords | ILK / paired helical filament / Alzheimer's disease / animal model / tau / aberrant phosphorylation / brain / learning and memory / タウタンパク質 / 痴呆 |
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| Research Abstract |
Integrin-linked kinase (ILK) is a focal adhesion serin/threonine protein kinase with an important role in integrin and growth factor signaling pathways. Recently, we demonstrated that ILK inactivation results in aberrant tau phosphorylation, which is identical to some of the aberrant phosphorylation sites in paired helical filaments in the brains of patients with Alzheimer's disease, via sustained activation of GSK-3β in cultured N1E-115 cells. In this study, we examined whether sustained inactivation of ILK leads to aberrant tau phosphorylation and produces paired helical filaments in mouse brain. Transfection and expression of a kinase-deficient mutant of ILK (DN-ILK), which behaves as a dominant negative, to mouse brain in vivo lead to inhibition of ILK activity and increase in active form of GSK-3β, and then induce aberrant tau phosphorylation in the hippocampus 3 wk after the transfection. However, the inhibition of endogenous ILK activity induced by DN-ILK is not retained and recovered to the basal level via a marked increase of endogenous ILK protein 12 wk after DN-ILK transfection. This compensatory mechanism leads the active form of GSK-3β to normal level and results in a decrease in the levels of aberrant tau phosphorylation. These results strongly suggest that ILK protects against aberrant tau phosphorylation via inhibition of GSK-3β activity in vivo. Although we could not create the mouse model for paired helical filaments in the brains of patients with Alzheimer's disease, our results imply that medical drugs to activate ILK activity might be effective in the therapy of patients with the early stage of Alzheimer's disease. Further studies are required to elucidate the compensatory mechanism after ILK inactivation in the brain.
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