1994 Fiscal Year Final Research Report Summary
Development of clinico-chemical and molecular-biological methods for diagnosis of Alzheimer's disease
| Project/Area Number |
04557013
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| Research Category |
Grant-in-Aid for Developmental Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Pathological medical chemistry
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
UEDA Kunihiro Kyoto Univ., Inst.for Chem.Res., Professor, 化学研究所, 教授 (00027070)
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| Co-Investigator(Kenkyū-buntansha) |
TANAKA Seigo Kyoto Univ., Inst.for Chem.Res., Assist.Prof., 化学研究所, 助手
OHYAMA Kunio Asahi Chemical Industry, Life Sci.Res.Lab., Head, 診断薬事業部・診断薬研究部, 課長
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| Project Period (FY) |
1992 – 1994
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| Keywords | Alzheimer's disease / Amyloid prescurosr protein gene / Gene analysis / Splicing / Apolipoprotein E gene / Risk factor / Amyotrophic lateral sclerosis / Superoxide dismutase-1 gene |
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| Research Abstract |
(1) Aberrant expression of amyloid beta protein precursor (APP) gene in Alzheimer's disease (AD) : We found a 1.5-fold elevation, on the average, of the ratio of APP mRNAs with and without a Kunitz-type protease inhibitor (KPI) domain in AD brains compared with controls. The ratio was also found to be elevated in control brains with aging, though 20-25 years later than in AD.The change of the ratio was most apparent in the gray matter of cerebral cortex including hippocampus known to be affected in dementia. Based on these findings, we proposed the APP mRNAs ratio to serve as a molecular index of the brain aging.
(2) No specific change in nucleotide sequences of APP gene in AD : We analyzed nucleotide sequences of the regions responsible for alternative splicing of APP gene transcript and producing distinct mRNAs with or without KPI domain in AD and control. There was no specific change found in the sequences among AD patients.
Increase of KPI fragments in cerebrospinal fluid (CSF) of AD : Assay of APP-derived KPI fragments using a newly invented trypsin-ELISA method revealed a significant increse of the fragments in the CSF of AD patients.
(4) Deviation of apolipoprotein E allele frequency in AD : We confirmed a 2-3-fold higher frequency of epsilon4 allele of apolipoprotein E (APOE) gene among late-onset AD patients, as reported for Americans, with Japanese cases. We further identified the epsilon4 allele homozygosity to be a particularly high risk factor for late-onset AD.
New mutation for amyotrophic lateral sclerosis (ALS) : We found a hitherto unknown mutation, Leu^<106>*Val (CTC*GTC) in the superoxide dismutase-1 gene in a familial ALS patient.
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