| Project/Area Number |
13210147
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | RIKEN |
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Principal Investigator |
TAKASHIMA Akihiko RIKEN, Lab for Alzheimer's Disease The Physical and Chemical Research, Laboratory Head, アルツハイマー病研究チーム, チームリーダー (00154774)
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| Co-Investigator(Kenkyū-buntansha) |
SAHARA Naruhiko RIKEN, Lab for Alzheimer's Disease The Physical and Chemical Research, Research Scientist, アルツハイマー病研究チーム, 研究員 (40261185)
崔 得華 独立行政法人理化学研究所, アルツハイマー病研究チーム, 研究員
エマヌエル プラネル 独立行政法人理化学研究所, アルツハイマー病研究チーム, 研究員
ISHIZUKA Koko RIKEN, Lab for Alzheimer's Disease The Physical and Chemical Research, Research Scientist, アルツハイマー病研究チーム, 研究員 (80373265)
CHUI De-Hua RIKEN, Lab for Alzheimer's Disease The Physical and Chemical Research, Research Scientist
PLANEL Emmanuel RIKEN, Lab for Alzheimer's Disease The Physical and Chemical Research, Research Scientist
催 徳華 独立行政法人理化学研究所, アルツハイマー病研究チーム, 研究員
プラネル エマヌエル 独立行政法人理化学研究所, アルツハイマー病研究チーム, 研究員
楯林 義孝 独立行政法人理化学研究所, アルツハイマー病研究チーム, 研究員 (80342814)
種村 健太郎 理化学研究所, アルツハイマー病研究チーム, 研究員 (20332322)
宮坂 知宏 理化学研究所, アルツハイマー病研究チーム, 研究員 (90342857)
孫 小燕 理化学研究所, アルツハイマー病研究チーム, 研究員 (50312278)
佐藤 慎二 理化学研究所, アルツハイマー病研究チーム, 研究員 (10322702)
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| Project Period (FY) |
2001 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥60,000,000 (Direct Cost: ¥60,000,000)
Fiscal Year 2004: ¥16,000,000 (Direct Cost: ¥16,000,000)
Fiscal Year 2003: ¥16,000,000 (Direct Cost: ¥16,000,000)
Fiscal Year 2002: ¥16,000,000 (Direct Cost: ¥16,000,000)
Fiscal Year 2001: ¥12,000,000 (Direct Cost: ¥12,000,000)
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| Keywords | Alzheimer's disease / GSK-3 / Neurofibrillary tangles / Tau / Aging / JNK / Aβ / Presenilin / 神経原線維変化 / 細胞骨格 / 痴呆 / FTDP-17 / GSK-3β / FTDP17 / マウスモデル / 行動異常 |
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| Research Abstract |
We generated the mouse overexpressing human 4 repeat tau driven by PDGF-β promoter, which contains V337M frontotemporal dementia-17(FTDP-17) mutation. The amount of expression was about 5-10% of endogenous mouse tau, and the accumulation of hyper-phosphorylated tau was seen in the hippocampus CA2 and 3 region and the cerebral cortex at 11 month old. At this age tau in Tg mouse became insoluble for SDS and form filamentous structure, and Tg mouse could form NFT with aging. The decrease in the neuronal activity in the hippocampus was observed in the electrophysiological experiments. In addition, Tg mice didn't show habituation, and significantly stay longer in open arm in elevated plus maze test. Thus, it was clarified that NFT formation reduced neural activity in hippocampus and caused behavioral disorder.
In case of the other tau Tg mouse overexpressed human 4 repeat tau with the R406W mutation under control of CAMK II promoter, the mouse model also showed NFT like pathology accompanying with memory deficit, which pathophysiological features are very similar to the patient of AD and R406W. In addition, we could find the activation of GSK-3b and JNK in neurons, which accumulate hyperphosphorylated tau, suggesting that GSK-3 and JNK might be involved in NFT formation.
To confirm the involvement of GSK-3 and JNK on NFT formation, we expressed JNK, deltaMEKK, GSK-3b, and human tau in COS7 cells. Tau showed the increased phosphorylation at 12 phosphorylation sites, including AT100 immunoreactive site, which is known as a peculiar antigen of PHF-tau seen in AD. SDS insoluble materials showed anti-phospho-tau immunoreactive aggregates. Thus, an excessive phosphorylation of Tau by GSK-3 β and JNK took part in NFT formation. In addition, when GSK-3 was activated by β amyloid, tau TG mouse resulted in the neurofibrillary tangle formation, the synapse loss, and the neuron death.
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