| Co-Investigator(Kenkyū-buntansha) |
TANAKA Toshihisa Osaka University Graduate School of Medicine, Lecturer, 医学系研究科, 講師 (10294068)
KUDO Takashi Osaka University Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (10273632)
TAKEDA Masatoshi Osaka University Graduate School of Medicine, Professor, 医学系研究科, 教授 (00179649)
OKOCHI Masayasu Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (90335357)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2003: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2002: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
Serum lipid profile, especially apolipoprotein levels, in patients with late-onset Alzheimer's disease (LOAD) is altered compared to non-demented healty subjects, and the notable changes are decreased apolipoprotein A-II and A-I levels. We focused on microsatellite of Apolipoprotein (APO) genes, and examined the relation between their microsatellites in APO genes and the development of LOAD. First of all, we found that the total doses of microsattellite repeat in APOA-II gene is inversely correlated with age at onset of LOAD among APOE-e4 carriers (p<O.OO1). This microsatellite locates spricing acceptor site of exon 3 of APOA-II gene, and the longer the microsatellite length was related to the increased amount of mRNA lacking exon 3 and decreased amount of intact mRNA. However, mRNA lacking exon 3 did not produce protein product of apolipoprotein A-II, and it was thought that the microsatellite length was correlated with the amount of apolipoprotein A-II. On the other hand, ** also exa
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mined the microsatellite of APOC-II gene, which harbors microsatellite after the first transcribed region, and it locates nearby Apolipoprotein E gene, a risk gene of LOAD. We found that the total doses of microsatellite repeat is also correlated with age at onset of LOAD (p<O.O0O1). This effect was also significant in APOE-e4 carriers. Plasma apolipoprotein C-II level was inversely correlated with the total doses of the microsatellite repeat (p<0.05). Therefore, we concluded that these microsatellite located in intronic sequences acts to modify the amount of expressed protein product. Since in aging, plasma apolipoprotein A-II decreases and plasma apolipoprotein C-II level increases, which could be enfluenced by aging factors. It has been shown that microsatellites tend to form Z-DNA structure. Therefore, microsatellite structure is targeted by aging factors, and likely participates as genetic factor modifed by aging in the development of LOAD. Our results suggest that some factors targeting microsatellite structure could be related with aging. Less
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