| Project/Area Number |
12210005
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
|
| Allocation Type | Single-year Grants |
|---|
| Review Section |
Biological Sciences
|
|---|
| Research Institution | University of Tokyo |
|---|
Principal Investigator |
IHARA Yasuo University of Tokyo, Graduate School of Medicine, Professor, 大学院医学系研究科, 教授 (60114386)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
MORISHIMA Maho University of Tokyo, Graduate School of Medicine, Lecturer, 大学院医学系研究科, 講師 (50204722)
FUNAMOTO Satoru University of Tokyo, Graduate School of Medicine, Instructor, 大学院医学系研究科, 助手 (10345043)
MIYASAKA Tomohiro University of Tokyo, Graduate School of Medicine, Instructor, 大学院医学系研究科, 助手 (90342857)
ITO Mamoru University of Tokyo, Graduate School of Medicine, Senior Scientist, 免疫研究室, 室長 (00176364)
FUJITA Shinobu Mitsubishi Kagaku Inst., Life Sciences, Senior Researcher, 生命科学研究所, 主任研究員 (30092323)
元永 耕三 東京大学, 大学院・医学系研究科, 助手 (20345044)
山崎 恒夫 東京大学, 大学院・医学系研究科, 助手 (80200658)
小山 文隆 東京大学, 大学院・医学系研究科, 講師 (40194641)
岡澤 均 東京大学, 医学部・附属病院, 助手 (50261996)
|
|---|
| Project Period (FY) |
2000 – 2004
|
| Project Status |
Completed (Fiscal Year 2004)
|
| Budget Amount *help |
¥144,200,000 (Direct Cost: ¥144,200,000)
Fiscal Year 2004: ¥35,200,000 (Direct Cost: ¥35,200,000)
Fiscal Year 2003: ¥35,200,000 (Direct Cost: ¥35,200,000)
Fiscal Year 2002: ¥35,200,000 (Direct Cost: ¥35,200,000)
Fiscal Year 2001: ¥38,600,000 (Direct Cost: ¥38,600,000)
|
|---|
| Keywords | Alzheimer's disease / Tau / Neurofibrillary tangles / Neuronal death |
|---|
| Research Abstract |
Discovery of various mutations in the tau gene among the families affected by frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) suggests gain-of-toxic function of wild-type or mutant tau as the mechanism for extensive neuronal loss. To learn about the role of tau in the tauopathy, we have generated animal models that express FTDP-17 mutant (P301L or R406W) tau.
1.We established transgenic mice expressing prion promoter-driven P301L mutant tau. The brains were sampled from those mice at various ages (3, 6, 12, 20, and 24 months) and analyzed by either biochemical or immunohistochemical methods. However, transgene-derived alterations, such as degeneration of neurons and deposition of tau, were not observed up to 24 months.
2.We generated transgenic nematode (Caenorhabditis elegans) expressing wild-type or mutant (P301L and R406W) tau in the touch (mechanosensory) neurons. Whereas the worm expressing wild-type tau showed only a small decrease in the touch response across the lifespan, the worm expressing mutant tau displayed a large and progressive decrease. When the touch neurons lost their function, neuritic abnormalities were prominent, and microtubular loss became remarkable in the later stage. A substantial fraction of degenerating neurons developed tau accumulation in the cell body and neuronal processes. This neuronal dysfunction is not related to the apoptotic process because little recovery from touch abnormality was observed in the ced-3 or ced-4-deficient background. Expression of GSK3 brought about slight deterioration in the touch response, while expression of HSP70 led to some improvement.
|
