| Project/Area Number |
13470196
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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 |
Psychiatric science
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| Research Institution | Osaka University |
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Principal Investigator |
TAKEDA Masatoshi Osaka University Graduate School of Medicine, Professor, 医学系研究科, 教授 (00179649)
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| Co-Investigator(Kenkyū-buntansha) |
KUDO Takashi Osaka University Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (10273632)
TANAKA Toshihisa Osaka University Graduate School of Medicine, Lecturer, 医学系研究科, 講師 (10294068)
中村 祐 奈良県立医科大学, 医学部, 講師 (70291440)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥16,000,000 (Direct Cost: ¥16,000,000)
Fiscal Year 2002: ¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 2001: ¥11,800,000 (Direct Cost: ¥11,800,000)
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| Keywords | Alzheimer disease / tau protein / phosphorylation / presenilin / oxidative stress / spoptosis / ribotoxic stress / endoplasmic reticulum stress |
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| Research Abstract |
Neurofibliraly tangles (NFTs) and neuronal cell death are hallmark of Alzheimer's disease (AD) and abnormal hyperphospholylated tau protein is the major subunit of NFT. However the mechanisms of phosphorylation of tau in neurodegenerative process of AD is unknown. We investigated the changes of phosphorylation of tau protein and neuronal cell death in SY5Y human neuroblastoma cells treated with peptidyltransferase inhibitors including anisomycin and T2-triol. Western blot analysis revealed that anisomycin and T2-triol induced activation of SAPK and p38 MAPK and hyperphosphorylation of tau protein at the M4 (Thr-231/Ser-235), the PHF-1 (Ser-396/404) and the S422 (Ser-422) site. The inhibitor of p38, SB203580, attenuated the phosphorylation of tau protein in this response, whereas an inhibition of GSK-3, lithium, did not. In this response the number of apoptotic cells visualized by Hoechst33342 was less than *he number of total dead cells visualized by Live/Dead kit (Molecular Probe), suggesting the non-apoptotoc cell death mechanism might be involved. This peptidyltransferase-inhibition is one kind of ribotoxic stresses. Further the cells were treated with rose bengal and light, and singlet oxygen was induced. Under this condition, ribosomal RNA was oxidized and tau protein was phosphorylated, probably through ribotoxic stress. In AD brain hyperphosphorylation of tau protein and neuronal cell death might be explained by this ribotoxic stress mechanism.
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