| Project/Area Number |
02455028
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
広領域
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| Research Institution | Tokyo Institute of Psychiatry |
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Principal Investigator |
YOSHIKAWA Kazuaki Dept. Molecular Biology, Director, 分子生物学研究部門, 副参事研究員 (30094452)
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| Co-Investigator(Kenkyū-buntansha) |
AIZAWA Takako Dept. Molecular Biology, Researcher, 分子生物学, 研究員
USAMI Mihoko Dept. Molecular Biology, Researcher, 分子生物学, 研究員
KAMETANI Fuyuki Dept. Molecular Biology, Researcher, 分子生物学, 主事研究員 (70186013)
MARUYAMA Kei Dept. Molecular Biology, Head, 分子生物学, 主任研究員 (30211577)
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| Project Period (FY) |
1990 – 1991
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| Project Status |
Completed (Fiscal Year 1991)
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| Budget Amount *help |
¥5,900,000 (Direct Cost: ¥5,900,000)
Fiscal Year 1991: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1990: ¥5,000,000 (Direct Cost: ¥5,000,000)
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| Keywords | Alzheimer's disease / amyloid protein / Gene transfection / Teratoma cells / Neural differentiation / Neurons / Aging / Degeneration / アルツハイマ-病 / テラト-マ細胞 / ニュ-ロン / ニュ-ロン変性 / アミロイド / 遺伝子発現 |
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| Research Abstract |
Alzheimer disease is characterized by the deposition of amyloid fibrils whose major constituent is beta protein. Beta-protein may be generated by abnormal proteolysis of the precursor, amyloid protein precursor (APP). Molecular mechanism of amyloid formation is as yet unclear at present. We have investigated the molecular mechanism of amyloidogenesis using cultured cell models. We have transfected APP complementary DNA (cDNA) to teratoma cells (P19) to establish the cell lines overexpressing APP. Our findings are as follows:
1) The endogenous level of APP 695 mRNA was markedly increased when P19 cells were induced to differentiate into neural cells. The pat- tern of APP 695 mRNA changes resembles that in differentiating neurons in vivo.
2) We transfected APP cDNA into undifferentiated P19 cells, and established stable transfectants. When the cells were treated to differentiate, almost all the differentiated neurons showed severe degeneration, which may be due to intracellular accumulations of potentially amyloidogenic fragments of APP.
3) The remaining (surviving) cells contained a high level of APP immunoreactivity in lysosome-like organelles. Therefore, if is likely that the cytotoxic fragments of APP may be generated in lysosomes.
These findings suggest a new concept that abnormal metabolism of APP in neurons generates cytotoxic fragments of APP, which cause neuronal death followed by amyloid formation in the extracellular space. The teratoma cells transfected with the APP gene is a useful tool for molecular dissection of the relationship between amyloidogenesis and neuronal degeneration.
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