2001 Fiscal Year Final Research Report Summary
Identification of the major in vivo ABl-42-degrading catabolic-system in brain parenchyma.
| Project/Area Number |
12672167
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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 |
医薬分子機能学
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| Research Institution | The Institute of Physical and Chemical Research |
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Principal Investigator |
IWATA Nobuhisa The Institute of Physical and Chemical Research, Laboratory for Proteolytic Neuroscience, Research Scientist, 神経蛋白制御研究チーム, 研究員 (70246213)
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| Co-Investigator(Kenkyū-buntansha) |
TSUBUKI Satoshi The Institute of Physical and Chemical Research, Laboratory for Proteolytic Neuroscience, Senior Technical staff, 神経蛋白制御研究チーム, テクニカルスタッフ(研究職) (20217368)
SAIDO Takaomi The Institute of Physical and Chemical Research, Laboratory for Proteolytic Neuroscience, Team Leader, 神経蛋白制御研究チーム, チームリーダー(研究職) (80205690)
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| Project Period (FY) |
2000 – 2001
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| Keywords | Alzheimers Disease / Amyloid-β ptide / Neutral Endopeptidase / Neprilysin / Knockout mice / Radio-label / Degradation / Aging |
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| Research Abstract |
Accumulation of amyloid-pβ peptide (Ap) in brain triggers the pathological cascade leading to Alzheimer' s disease. To examine the mechanism of AB catabolism, we analysed the fate of multiply radio-labeled 3H/14C-Aβl-42 injected into rat hippocampus and identified neutral endopeptidase (s) similar or identical to neprilysin as the rate-1imiting peptidase using a panel of peptidase inhibitors. Chronic infusion of thiorphan, a specific inhibitor of neprilysin, into rat hippocampus caused accumulation of endogenous AB. To further identify the thiorphan-sensitive peptidase, we analysed ABl-42 catabolism by six recombinant thiorphan-sensitive peptidases in neutral endopeptidase family. Neprilysin degraded AB most rapidly and efficiently among them. Neprilysin-deficient mice showed significantly reduced ability to catabolize AB. We also observed a gene dosage-dependent clevation of the endogenous AB levels (-/- > +/- > +/+) in the mouse brains. The increase in the AB42 level in the neprilysin-deficient mouse brain was comparable to that in the mice carrying PSI mutation. Moreover, the regional Ap levels in wild-type mouse brain were in the order of hippocampus > cortex > striatum/thalamus > cerebellum and this tendency was markedly exaggerated in the neprilysin-deficient mice. In the experiments using aged mice, neprilysin activity and its protein content in hippocampus were reduced by 200% at 30 months-old ages, compared to 2 months-old ages. The neprilysin activity in cortex was also slightly but significantly reduced with aging, whereas those in other regions were not changed. These observations suggest that the neprilysin is the major AB-degrading enzyme in brain despite the molecular redundancy of the neprilysin family and that reduction of neprilysin activity particularly in the regions vulnerable to AB pathology will contribute to Alzheimer' s disease development by promoting AB deposition.
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[Publications] Takaki, Y., Iwata, N., Tsubuki S. Taniguchi, S., Toyoshima S., Lu, B., Gerard, N.P., Gerard C., Lee, H.-J., Shirotani K., and Saido T.C: "Biochemical identification of the neutral endopeptidase family member responsible for the catabolism of amyloid PB peptide in brain."J. Biochem.. 28(6). 897-902 (2000)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Fukami S., Watanabe K., Iwata N. Haraoka J., Lu B., Gerard N.P., Gerard C., Fraser P., Westaway D., St. George-Hyslop P., and Saido T.C.: "AB-degrading endopeptidase, neprilysin, in mousebrain : Synaptic and axonal localization inversely correlating with AB pathology."Neurosci. Res. (in press).
Description
「研究成果報告書概要(欧文)」より
