2001 Fiscal Year Final Research Report Summary
Neurodegenerative diseases and protein folding governed by copper ion
| Project/Area Number |
12672084
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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 |
Physical pharmacy
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| Research Institution | Tohoku University |
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Principal Investigator |
MIURA Takashi Tohoku University, Graduate School of Pharmaceutical Sciences, Assistant Professor, 大学院・薬学研究科, 講師 (30222318)
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| Project Period (FY) |
2000 – 2001
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| Keywords | neurodegenerative diseases / Alzheimer's disease / metal / histidine / tyrosine / Raman spectroscopy |
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| Research Abstract |
1. Aggregation of amyloid β-peptide (Aβ), a key pathological event in Alzheimer's disease, has been shown in vitro to be profoundly promoted by Zn(II). This fact suggests that some factors in the normal brain protect Aβ from the Zn(II)-induced aggregation. In this study, it has been demonstrated that Cu(II) effectively inhibits the Aβ aggregation by competing with Zn(II) for histidine residues. The Raman spectrum of a metal-Aβ complex in the presence of both Zn(II) and Cu(II) shows that the cross-linking of Aβ through binding of Zn(II) to the Nτ atom of histidine is prevented by chelation of Cu(II) by the Nπ atom of histidine and nearby amide nitrogens. The inhibitory effect is strongest at a Cu/Aβ molar ratio of around four. Above this ratio, Cu(II) itself promotes the Aβ aggregation by binding to the phenolate oxygen of Tyr10. These results emphasize the importance of regulation of Cu(II) levels to inhibit Aβ aggregation, and are consistent with an altered metal homeostasis in Alzheimer's disease.
2. The Fe(III) ion binds to Aβ and induces significant aggregation of the peptide. In order to understand the role of Fe(III) in Aβ aggregation, the Fe(III)-binding mode of Aβ has been examined by Raman spectroscopy. The Raman spectra of Fe(III)-Aβ complexes excited at 514.5 nm are dominated by resonance Raman bands of metal-bound tyrosinate, evidencing that the Fe(III) ion primarily binds to Aβ via the phenolic oxygen of Tyr10. On the other hand, histidine ewsidues in the N-terminal hydrophilic region of Aβ do not bind to Fe(III). These results are in sharp contrast to the Zn(II)-induced aggregation of Aβ, in which histidine residues act as the primary metal binding sites.
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Research Products
(8 results)
