| Project/Area Number |
62480210
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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 |
Neurology
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| Research Institution | Tokyo Metropolitan Institute of Gerontology |
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Principal Investigator |
IHARA Yasuo Tokyo Metropolitan Institute of Gerontology, 臨床系2生理, 室長 (60114386)
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| Co-Investigator(Kenkyū-buntansha) |
関 俊子 東京都老人総合研究所, 臨床系2生理, 研究助手
三浦 玲子 東京都老人総合研究所, 臨床系2生理, 研究助手
OGAWARA Midori see above, 臨床系2生理, 研究助手 (60100111)
TAMAOKA Akira see above, 臨床系2生理, 研究員 (50192183)
MORI Hiroshi see above, 臨床系2生理, 研究員 (10159189)
MIURA Reiko see above
SEKI Toshiko see above
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| Project Period (FY) |
1987 – 1988
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| Project Status |
Completed (Fiscal Year 1988)
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| Budget Amount *help |
¥4,500,000 (Direct Cost: ¥4,500,000)
Fiscal Year 1988: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1987: ¥3,000,000 (Direct Cost: ¥3,000,000)
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| Keywords | Alzheimer's disease / ubiquitin / tau / protein sequencing / protein sequeneing / protein sequecing / curly fiber |
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| Research Abstract |
One of the hallmarks of Alzheimer's disease (AD) is the progressive accumulation of unusual neuronal fibers, termed paired helical filaments (PHF). Since the concentration of PHF in cerebral cortex was suggested to well correlated with the degree of dementia, much effort has been concentrated to the elucidation of the nature of PHF. However, the component analysis of PHF has been only slowly progressing because of remarkable insolubility of PHF.
Immunocytochemical studies using antibodies to cytoskeletal proteins provided conflicting data on the components of PHF due solely to immunological cross-reactivities. To avoid such ambiguity, we developed a protein chemical approach to the identification of the PHF components. After treatment with formic acid, PHF were digested with lysylendopeptidase and the produced peptides were separated by PHLC. All major peaks were analyzed for their amino acid compositions and sequences. From the PHF digests, proteolytic fragments of Ubiquitin, tau and p
… More
rotein were sequenced. ubiquitin appears to be of a conjugated form in PHF, while its target protein remains unidentified. Tau is integrated into PHF at its carboxyl third. the presence of protein fragments is best interpreted as being due to contamination of amyloid filaments in the PHF preparation. Thus, ubiquitin and tau are the two definite components of PHF.
We also re-examined AD brain sections using antibodies to human tau, one of the definite components of PHF. The tau immunostaining revealed extensive meshworks throughout AD cortex in addition to senile plaques and neurofibrillary tangles. The meshwork was most dense in layers 3 and 5 of the association cortex, suggesting a close relationship with pyramidal cells. Further observations showed that the meshwork consists of innumerable abnormaly curly fibers which were 5-30 um long and often swollen at the one end. The curly fibers appears to come from pyramidal cell bodies and their dendrites. These morphological features strongly suggest that these curly fibers represent somatodendritic sprouting. This hypothesis could explain why several fetal antigens are expressed in the AD brain. This is also compatible with a recent unexpected finding that nerve growth activities are increased in AD brain compared with normal controls. Less
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