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Elucidation of the mechanism underlying neuro-injury and dementia caused by mitochondrial aldehyde dehydrogenase deficiency

阐明线粒体醛脱氢酶缺乏引起的神经损伤和痴呆的机制

基本信息

批准号：
11670647
负责人：
KAMINO Kouzin
金额：
$ 2.3万
依托单位：
Osaka University (2001)Kanazawa Medical University (2000)Nippon Medical School (1999)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

项目摘要

Mitochondrial aldehyde dehydrogenase (ALDH2) deficiencywas fond to be a genetic risk for late-onset Alzheimer's disease. Estimation in 127 patients and 281 controls indicated that life-time risk for Alzheimer's disease is 10.9 times higher by APOE-ε4 allele than the other APOE allele and 2.1 times higher by ALDH2^*2 allele ( defective allele for the ALDH2 gene) than by ALDK2^*1 allele ( normal allele for the ALDH2 gene). A dominant negative mouse ALDH2 cDNA expression vector was constructed using mouse ALDH2 cDNA incorporating the last 5th codon with a Lys residue. Using this vector transgenic mice defective in ALDH2 expression were made, but F1 mice were small and did not grown up, Suggesting that defect in ALDH2 induces a severe disturbance of growth;. In cultured cell experiment using PC12 cells, it was found that defect in ALDH2 causes vulnerability for oxidative stress. Based on these results, defect in A1JDH2 is caused by fundamentally free radical stress. In that, defect in ALDH2 results in slower aldehyde metabolism, leading to aldehyde accumulation and resulting overproduction of free radical. Free radical induces mitochondrial membrane injury and DNA injury, and finally apoptosis Neuronal cell is apt to produce free radicals because of demanding more energy than the other tissuses. It was known that APOE-ε4 allele induces lowering the ability to process free radcal. In conclusion, APOE-ε4 and ALDH2*2 alleles are the risk for Alzheimer's disease, by lowering the ability to process free radical, and vulnerable to oxidative stress.

线粒体醛脱氢酶（ALDH2）缺陷被认为是迟发性阿尔茨海默病的遗传风险。127例患者和281例对照者的估计表明，APOE-ε4等位基因的终生阿尔茨海默病风险是其他APOE等位基因的10.9倍，ALDH2^*2等位基因（ALDH2基因的缺陷等位基因）的终生阿尔茨海默病风险是ALDH2基因的正常等位基因ALDH2^* 1等位基因的2.1倍。以小鼠ALDH2 cDNA为载体，结合最后5个密码子和一个Lys残基，构建了小鼠ALDH2显性阴性表达载体。利用该载体制备了ALDH2表达缺陷的转基因小鼠，但F1小鼠体积小，不能长大，提示ALDH2表达缺陷引起了严重的生长障碍；在PC12细胞的培养细胞实验中，发现ALDH2缺陷导致氧化应激易感性。综上所述，A1JDH2的缺陷主要是由自由基胁迫引起的。其中，ALDH2缺陷导致醛代谢减慢，醛积累，导致自由基过量产生。自由基诱导线粒体膜损伤和DNA损伤，最终导致细胞凋亡。神经细胞比其他组织需要更多的能量，因此更容易产生自由基。已知APOE-ε4等位基因导致自由基处理能力降低。综上所述，APOE-ε4和ALDH2*2等位基因是阿尔茨海默病的风险基因，通过降低自由基处理能力，易受氧化应激的影响。