| Project/Area Number |
07557332
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 試験 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Osaka University |
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Principal Investigator |
YOSHIKAWA Kazuaki Institute for Protein Research, Osaka University, Professor, たんぱく質研究所, 教授 (30094452)
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| Co-Investigator(Kenkyū-buntansha) |
HAYASHI Yokichi Nagano College of Nursing, Associate Professor, 助教授 (70173044)
MIKI Naomasa Medical School, Osaka University, Professor, 医学部, 教授 (40094445)
UETSUKI Taichi Institute for Protein Research, Osaka University, Instructor, たんぱく質研究所, 助手 (20260309)
TANIURA Hideo Institute for Protein Research, Osaka University, Instructor, たんぱく質研究所, 助手 (80263325)
NIINOBE Michio Institute for Protein Research, Osaka University, Associate Professor, たんぱく質研究所, 助教授 (80135748)
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| Project Period (FY) |
1995 – 1996
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| Project Status |
Completed (Fiscal Year 1996)
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| Budget Amount *help |
¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1996: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Keywords | Alzheimer's disease / amyloid protein / APP / neurons / adenovirus vector / neurodegeneration / brain / gene transfer / 胚性がん細胞 / 脳病理 / 培養細胞 / 発現制御 / アデノウイルス |
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| Research Abstract |
Alzheimer's disease (AD) is characterized by the progressive dementia as a result of massive neuronal death in the brain. Clarification of the pathogenesis of this disease is one of the most urgent medical problems. Amyloid beta protein (Abeta) is the principal component of amyloid fibrils that are deposited in the brain affected by AD.Thus Abeta might be closely associated with the pathogenesis of the disease. Abeta is derived from the precursor, termed the amyloid precursor protein (APP). In an attempt to elucidate the pathological implications of intracellular accumulation of APP in postmitotic neurons, we transferred APP cDNA into rat hippocampal neurons under cultured conditions by using a replication-defective adenovirus vector. Neurons accumulating the membrane-bound form of APP showed greater responsiveness to exogenous glutamate than non-expressing control neurons, suggesting that elevated calcium levels potentially cause neurodegeneration. Moreover, we demonstrated that overexpression of APP by the same APP-expressing adenovirus vector induces death of human cultured neurons derived from human embryonal carcinoma cells within several days. When an APP-expressing adenovirus wazs injected into a rat hippocampus, some of the infected neurons in the hippocampal formation underwent severe degeneration displaying shrunk perikarya along with synaptic abnormalities in a few days. These experimental systems enable us to study detailed molecular mechanisms of APP-induced neurodegeneration, and will be useful for studies on pathogenesis of AD and development of therapeutics.
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