1991 Fiscal Year Final Research Report Summary
Molecular mechanism on the pathogenesis of Alzheimertype dementia
| Project/Area Number |
01044018
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| Research Category |
Grant-in-Aid for international Scientific Research
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| Allocation Type | Single-year Grants |
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| Section | Joint Research |
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| Research Institution | Tohoku University |
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Principal Investigator |
KOGURE Kyuya Dept. Neurology, Tohoku University, Japan, 医学部, 教授 (20133936)
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| Co-Investigator(Kenkyū-buntansha) |
TANZI R. E. Dept. Neurology, Harvard Medical School, U. S. A., 医学部(米国), 助手
HYSLOP P.H.S トロント大学, 医学部(カナダ), 助手
ABE Koji Dept. Neurology, Tohoku University, Japan, 医学部, 助手 (20212540)
ST. GEORGE-HYSLOP Ph Dept. Neurology, University of Toronto, Canada
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| Project Period (FY) |
1989 – 1991
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| Keywords | Alzheimer's disease / amyloid precursor protein / heat shock protein / protease inhibitor / ischemia |
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| Research Abstract |
Alzheimer's disease (AD) is pathologically characterized by numerous senile plaques and neurofibrally tangles in the brain. Beta-amyloid is the core. Component of senile plaques surrounded by clusters of degenerating neurites, and is generated by proteolysis of the precursor protein (amyloid precursor. protein, APP). It has been elucidated that AD is not a single homogeneous disorder using genetic, linkage studies (St. George-Hyslop et al.). APP plays an important role in the deposition of beta-amyloid in senile plaques. An attempt to examine a possible relationship between APP induction and heat shock stress was performed in cultured human lymphoblastoid cells., APP mRNA was induced by heat shock treatment after the induction of HSP70 mRNA in Northern blot analysis, suggesting that a role of heat shock response in an induction of APP (Abe et al., 1991). An induction of APP mRNA was examined in a middle cerebral artery occlusion model of rats. With persistent focal ischemia, APP mRNA s
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pecies which contain a Kunitz-type protease. inhibitor (KPI) domain were induced in the rat cerebral cortex from 1 to 21 days after the insult with a maximum at 4 days, while total amounts of APP mRNA did not change. These results suggest a selective role of APP species which contain the KPI domain in focal cerebral ischemia.
Hippocampal CA1 cells are most vulnerable among cell populations in brain after ischemia, and are most involved in AD brain with numerous senile plaques and tangles. Heat shock protein (HSP) plays an important role in stress response of cells. Inductions of HSP70 and APP mRNAs within the CA1 and the parietal cortical cells were examined using Northern blot analysis. In contrast to the induction of HSP70 mRNA, no induction was observed in APP mRNA. The CA1 cells produced less amount of HSP70 mRNA than cortical cells at 8 hr after the transient ischemia, suggesting that the regional difference in the induction of HSP70 mRNA may relate to the regional difference of the vulnerability of neuronal cells after transient ischemia. An in situ hybridization study using HSP70 and HSC70 cDNA, . clones which we recently isolated from gerbil brain revealed that the production of HSP70 and HSC70 mRNA were disturbed in CA1 cells after ischemia, suggesting that CA1 cells are vulnerable at both transcriptional and translational levels of gene expressions after brief period of ischemia. These results are very important discovery to understand the mechanism why hippocampal CA1 cells are most vulnerable after ischemia and most involved in AD brain. Less
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