2002 Fiscal Year Final Research Report Summary
Aldehydes accumulated in mitochondria as risk factors to neurodegenerative diseases
| Project/Area Number |
12470144
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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 | Department of Biochemistry and Cell Biology, Institute of Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School |
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Principal Investigator |
OHTA Shigeo Nippon Medical School, Institute of Gerontology, Professor, 老人病研究所, 教授 (00125832)
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| Co-Investigator(Kenkyū-buntansha) |
OHOSAWA Ikurho Nippon Medical School, Institute of Gerontology, 老人病研究所, 助手 (30343586)
KANAMORI Takashi Nippon Medical School, Institute of Gerontology, 老人病研究所, 助手 (30333115)
ASHO Sadamitsu Nippon Medical School, Institute of Gerontology, 老人病研究所, 助教授 (70167914)
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| Project Period (FY) |
2000 – 2002
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| Keywords | aldehyde dehydrogenase / Alzheimer's disease / mitochondria / 4-hydroxy-2-nonenal / oxidative stress / cohort study / lipid peroxide / 過酸化脂質 |
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| Research Abstract |
Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is involved in ethanol metabolism by playing a major role in acetaldehyde detoxification : A polymorphism of the ALDH2 gene is specific to north Asians. Sensitivity to ethanol is highly associated with this polymorphism (ALDH2^*2 allele), which is responsible for a deficiency of ALDH2 activity. We at first show that this deficiency influences the risk for late-onset Alzheimer's disease (LOAD) by a case-control study in a Japanese population. In a comparison of 447 patients with sex, age and region-matched non-demented controls, the genotype frequency for carrying the ALDH2^*2 allele was significantly higher in the patients than in the controls (p=0.001). Next, we examined the combined effect of the ALDH2^*2 and apolipoprotein E 4 allele (APOE-e4), which has been confirmed be a risk factor for LOAD. The ALDH2^*2 allele more significantly affected frequency and onset-age in patients with APOE-e4 than without. These results indicate that the ALDH2 deficiency is a risk factor for LOAD, acting synergistically with the APOE-e allele. Next, to elucidate the molecular mechanism involved, we obtained ALDH2-deficient cell lines by introducing mouse mutant Aldh2 cDNA into PC12 cells. We speculate that ALDH2 may function to oxidize toxic aldehyde derivatives. Then, we found that the ALDH2-deficient transfectants were highly vulnerable to exogenous 4-hydroxy-2-nonenal, an aldehyde derivative generated from peroxidized fatty acids. In addition, the ALDH2-deficient transfectants were sensitive to oxidative insult induced by antimycin A, accompanied by an accumulation of proteins modified with 4-hydroxy-2-nonenal. Mitochondrial ALDH2 functions as a protector against oxidative stress.
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