2003 Fiscal Year Final Research Report Summary
Molecular mechanisms of γ-cleavage for the generation of amyloid β-protein
| Project/Area Number |
14580737
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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 |
Neurochemistry/Neuropharmacology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
MORISHIMA Maho The University of Tokyo, Graduate School of Medicine, Lecturer, 大学院・医学系研究科, 講師 (50204722)
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| Project Period (FY) |
2002 – 2003
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| Keywords | amyloid β-protein / Alzheimer's disease / γ-cleavage / presenilin / APP |
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| Research Abstract |
To understand molecular mechanisms of the proteolytic processing of APP (generation of Aβ) by presenilin-dependent γ-secretase, the relationship between γ-and γ' (ε)-cleavages of APP was investigated.
1. Amino acid substitutions in the vicinity of γ'-cleavage sites of APP altered γ'-cleavage sites as well as γ-cleavage sites, resulting in altered proportions of Aβ42 production.
2. Effects of familial Alzheimer's disease-associated mutations of APP and presenilins on γ-and γ'-cleavage sites were investigated. All the mutations examined here altered γ-cleavage sites and increased the proportion of Aβ42 production. Those mutations altered also γ'-cleavage sites and caused an increase in the proportion of CTFγ49-99 production. Although a potential link between the production of Aβ42 and CTPγ49-99 was observed, the proportion of Aβ4O and Aβ42 did not faithftully reflect that of CTFγ50-99 and 49-99.
These results indicate an intimate interrelation between γ-and y '-cleavages.
3. To evaluate the hypothesis that y '-cleavage precedes γ-cleavage, we sought to find an intermediate product, Aβ species longer than Aβ42/43. Using newly developed urea gel systems and an N-end-specific Aβ monoclonal antibody, the longer Aβs, Aβ1-43, Aβ1-45, Aβ1-46, and Aβ1-48, were identified unambiguously within the various cell types. The precise analysis of those longer Aβs suggests that multiple γ-secretase-dependent cleavage sites are present between γ-and 'γ'-cleavage sites of APP and that APP is cleaved successively at every three residues from the carboxyl-terminus generated by γ'-cleavage.
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Research Products
(12 results)
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[Publications] Sato T, Dohmae N, Qi Y, Kakuda N, Misonou H, Mitsumori R, Maruyama H, Koo EH, Haass C, Takio K, Morishima-Kawashima M, Ishiura S, Ihara Y: "Potential link between amyloid β-protein 42 and C-terminal fragment γ49-99 of β-amyloid precursor protein."J.Biol.Chem.. 278. 24294-24301 (2003)
Description
「研究成果報告書概要(和文)」より
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[Publications] Sato T, Dohmae N, Qi Y, Kakuda N, Misonou H, Mitsumori R, Maruyaina H, Koo EH, Haass C, Takio K, Morishima-Kawashima M, Ishiura S, Ihara Y: "Potential link between amyloid β-prorein 42 and C-terminal fragment γ49-99 of β-amyloid precursor protein."J Biol Chem. 278(27). 24294-24301 (2003)
Description
「研究成果報告書概要(欧文)」より
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