2001 Fiscal Year Final Research Report Summary
Elucidation of the mechanism underlying neuro-injury and dementia caused by mitochondrial aldehyde dehydrogenase deficiency
| Project/Area Number |
11670647
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurology
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| Research Institution | Osaka University (2001)
Kanazawa Medical University (2000)
Nippon Medical School (1999) |
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Principal Investigator |
KAMINO Kouzin Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (40307955)
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| Co-Investigator(Kenkyū-buntansha) |
OHTA Shigeo Nippon Medical School, Institute of Gerontology, Professor, 老人病研究所, 教授 (00125832)
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| Project Period (FY) |
1999 – 2001
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| Keywords | Alzheimer / aldehyde dehydrogenase / mitochondria / free radical / neuronal death / apolipoprotein E / tansgenic / apoptosis |
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| Research Abstract |
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.
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