| Project/Area Number |
16590816
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurology
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| Research Institution | Niigata University |
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Principal Investigator |
IKEUCHI Takeshi Niigata University, Brain Research Institute, Assistant, 脳研究所, 助手 (20372469)
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| Co-Investigator(Kenkyū-buntansha) |
成瀬 聡 新潟大学, 医歯学総合病院, 講師 (70313541)
下畑 享良 新潟大学, 脳研究所, 助手 (60361911)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 2004: ¥1,100,000 (Direct Cost: ¥1,100,000)
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| Keywords | Alzheimer disease / Transcription / Amyloid precursor protein / Neuronal cell death / Presenilin |
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| Research Abstract |
In this study, we investigated whether transcriptional impairment is involved in pathogenesis for Alzheimer disease. We established cell lines that stably express familial Alzheimer disease (FAD)-linked presenilin-1 (PS1) mutation. Using those cells, we analyzed transcription activation which is regulated by γ-secretase-dependent intramembranous cleavage of amyloid precursor protein (APP) and Delta-1. We also determined nuclear localization of intracellular domain (ICD) of APP and Delta-1 upon γ-secretase cleavage.
Cells expressing FAD-linked PS1 mutants, produced less amounts of ICD of APP as well as Delta-1 compared to those expressing wild-type. The intracellular fragments of APP and Delta-1 by γ-secretase cleavage were predominantly observed in nucleus. Luciferase reporter assay using Gal4-VP16 fusion proteins (APP-Gal4-VP16 and Delta1-Gal4-VP16), revealed FAD-linked PS1 mutants showed less activation of transcription.
These results suggest the possibility that transcriptional impairment is involved in pathogenesis for Alzheimer disease caused by FAD-linked PS1 mutation. Although the targets of transcriptional factors activated by APP and Delta-1 γ-secretase remain unknown, CREB regulated transcriptional factors were candidates and should be investigated.
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