11 固体NMRならびにESRによるβアミロイド(Aβ42)の毒性コンホメーションの解析(口頭発表の部)

• 入江 一浩

  京大院農

• 増田 裕一

  京大院農

• 村上 一馬

  京大院農

• 上村 諭子

  京大院農

• 大東 肇

  京大院農

• 原 英之

  ブルカー・バイオスピン

• 大橋 竜太郎

  京大院理

• 中西 梓

  京大院理

• 竹腰 清乃理

  京大院理

書誌事項

タイトル別名

• 11 Analysis of Toxic Conformation of β-amyloid (Aβ42) by Solid-state NMR and ESR

抄録

Aggregation of the 42-mer amyloid β (Aβ42) plays a central role in the pathogenesis of Alzheimer's disease. Our recent research on the systematic replacement of Aβ42 with proline suggested that the formation of a turn structure at Glu-22 and Asp-23 could be essential to the potent aggregative ability and neurotoxicity of Aβ42. We verified the existence of this turn structure in the minor conformer of wild-type Aβ42 and E22K-Aβ42 (Italian mutation), by solid-state NMR using dipolar assisted rotational resonance (DARR). In E22K-Aβ42, the ionic interaction between Lys-22 and Asp-23 might promote the turn formation at this site. In order to identify the toxic conformation of Aβ42, we synthesized Aβ42-lactam(22K-23E) as a conformationally restricted analogue of the minor conformer, whose side chains of Lys-22 and Glu-23 are linked with an amide bond. Aβ42-lactam(22K-23E) showed much stronger aggregative ability and neurotoxicity than E22K-Aβ42. This implies that the minor conformer with a turn at Glu-22 and Asp-23 of Aβ42 should be considered as a toxic form. Neurotoxicity of Aβ42 is closely related to the radicalization at both Tyr-10 and Met-35. Our previous study reminds us that the S-oxidized radical cation at position 35, the ultimate toxic radical species, would be produced effectively through oxidation by the phenoxy radical at position 10 in the toxic conformer. Electron spin resonance (ESR) spectrometry using spin-labeling with MTSSL revealed that these residues are close to each other in Aβ42. This finding clearly accounts for the reason why the toxic conformer is more pathogenic than the physiological one.

収録刊行物

• 天然有機化合物討論会講演要旨集

  天然有機化合物討論会講演要旨集 49 (0), 61-66, 2007

  天然有機化合物討論会実行委員会

詳細情報

• CRID: 1390001206079575424
• NII論文ID: 110006682741
• DOI: 10.24496/tennenyuki.49.0_61
• ISSN: 24331856
• 本文言語コード: ja
• データソース種別:
  • JaLC
  • CiNii Articles
• 抄録ライセンスフラグ: 使用不可