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Development of clinico-chemical and molecular-biological methods for diagnosis of Alzheimer's disease

开发诊断阿尔茨海默病的临床化学和分子生物学方法

基本信息

批准号：
04557013
负责人：
UEDA Kunihiro
金额：
$ 7.23万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Developmental Scientific Research (B)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1994
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-04557013/
关键词：
Alzheimer's disease Amyloid prescurosr protein gene Gene analysis Splicing Apolipoprotein E gene Risk factor Amyotrophic lateral sclerosis Superoxide dismutase-1 gene スーパーオキシドジスムターゼ-1遺伝子 βアミロイド APP プロテアーゼインヒビターアポリポ蛋白E 遺伝子型遺伝子

项目摘要

(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.

(1)阿尔茨海默病（AD）中淀粉样β蛋白前体（APP）基因的异常表达：与对照组相比，我们发现AD脑中有和没有Kunitz型蛋白酶抑制剂（KPI）结构域的APP mRNA的比例平均升高1.5倍。该比率也被发现在对照组大脑中随着年龄的增长而升高，尽管比AD晚了20-25年。该比率的变化在大脑皮层的灰质中最明显，包括已知在痴呆症中受影响的海马体。基于这些发现，我们提出APP mRNA比率作为脑老化的分子指标。(2)AD中APP基因核苷酸序列无特异性变化：我们分析了AD和对照中负责APP基因转录物选择性剪接并产生不同mRNA（含或不含KPI结构域）的区域的核苷酸序列。AD患者脑脊液（CSF）中KPI片段的增加：用新发明的胰蛋白酶-ELISA方法检测APP衍生的KPI片段，发现AD患者CSF中KPI片段显著增加。(4)AD中载脂蛋白E等位基因频率的偏差：我们证实，在晚发型AD患者中，载脂蛋白E（APOE）基因的epsilon 4等位基因频率高出2-3倍，与美国人和日本病例的报告相同。我们进一步确定ε 4等位基因纯合性是迟发性AD的一个特别高的危险因素。肌萎缩侧索硬化症（ALS）的新突变：我们发现了一个迄今未知的突变，Leu^<106>* 瓦尔（CTC*GTC）的超氧化物歧化酶-1基因在家族性ALS患者。