| Project/Area Number |
17028032
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Osaka University |
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Principal Investigator |
TOHYAMA Masaya Osaka University, Graduate school of medicine, Professor (40028593)
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| Co-Investigator(Kenkyū-buntansha) |
MORI Yasutake Osaka university, Graduate school of medicine, Associate Professor (00343252)
INOUE Kiyoshi Osaka university, Graduate school of medicine, Assistant Professor (20342719)
MATSUZAKI Shinsuke Osaka university, Graduate school of medicine, Assistant Professor (60403193)
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| Project Period (FY) |
2002 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥49,200,000 (Direct Cost: ¥49,200,000)
Fiscal Year 2006: ¥24,600,000 (Direct Cost: ¥24,600,000)
Fiscal Year 2005: ¥24,600,000 (Direct Cost: ¥24,600,000)
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| Keywords | endoplasmic reticulume (ER) / ER stress / caspase-4 / Alzheimer's disease (AD) / HMGAla / presenilin-2 splice valiants (PS2V) / cell death / therapy / アルツハイマー病 / 蛋白質品質管理機構 / カスペース4 / カスペース3 / カスペース9 / チトクロームC / プレセニリン1変異体 / 神経細胞死 / プレセニリン2スプライシング変種 |
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| Research Abstract |
In this research, we examined the involvement of to the endoplasmic reticulum (ER) stress in both familial and sporadic Alzheimer's disease (AD). As the resulrts, we showed that familial AD-linked presenilin-1 (PS1) mutation induced the fragility to the ER stress and that one of the presenilin-2 (PS2) splice valiants (PS2V), which were observed in the sporadic AD patient brains, also caused the fragility to the ER stress. Further studies elucidated that hydroxy radicals caused by hypoxia, metals, etc. induced HMGAla protein resulting in the aberrant splicing variant (PS2V). These results suggest the inhibition of HMGAla protein as the new therapy for sporadic AD. Next, we investigated the apoptosis pathway under the ER stress and found that caspase-4 mediates ER stress induced- and β-amyloid induced-apoptotic signaling in human cells. These results suggest the involvement of ER stress and caspase-4 in the cell death observed in AD. Thus, we studied the activation of caspase-4 in the familial AD-linked PS1 mutation (ΔE9). Cleavage of caspase-4 under ER stress was enhanced by the overexpression of the familial AD-linked mutation (ΔE9), showing that caspase-4 is a key caspase involved in the apoptotic signaling of AD. We also showed that the overexpression of caspase-4 induced cleavage of caspase-9 and caspase-3 without releasing cytochrome-c from the mitochondria. These results also suggest that the regulation of activated caspase-4 should be one of the new therapies for AD.
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