2020年10月7日
Synthetic and Biophysical Studies on the Toxic Conformer in Amyloid β with the E22Δ Mutation in Alzheimer Pathology
ACS Chemical Neuroscience
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- 巻
- 11
- 号
- 19
- 開始ページ
- 3017
- 終了ページ
- 3024
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1021/acschemneuro.0c00331
- 出版者・発行元
- American Chemical Society (ACS)
The toxic conformer of the 40- or 42-mer-amyloid β-proteins (Aβ) (Aβ40, Aβ42) with a turn at positions 22 and 23 plays a role in oligomer formation, leading to neurotoxicity as part of the pathogenesis of Alzheimer's disease (AD). A deletion mutant at Glu22 (E22Δ) of Aβ, known as an Osaka mutation, accelerates oligomerization. Although E22Δ-Aβ has not been found to be toxic to cultured neuronal cells and is instead synaptotoxic in long-term potentiation, there is no information on the toxic conformer of E22Δ-Aβ in AD. The site-directed spin labeling study of E22Δ-Aβ40 by continuous wave-electron spin resonance (CW-ESR) spectroscopy in part showed the spatial proximity between positions 10 and 35, which are characteristic of the toxic conformation of Aβ, indicating the existence of a toxic conformer of Aβ with the E22Δ mutation. To obtain structural insight, E22Δ-Aβ42 substitutes with proline (F20P, A21P, D23P, and V24P), in which proline is known as a turn inducer but is a β-sheet breaker, were synthesized. An enzyme immunoassay using the 24B3 antibody recognizing toxic conformer of Aβ was carried out. 24B3 reacted with these substitutes of E22Δ-Aβ42 as well as E22Δ-Aβ42 in a similar manner to WT-Aβ42. Notably, only A21P-E22Δ-Aβ42 exhibited strong neurotoxicity in rat primary neurons after 8 days of incubation, with potent high-order oligomerization compared with E22Δ-Aβ42. These results suggest that E22Δ-Aβ42 could enhance neurotoxicity by generating a toxic oligomer conformation with a turn near position 21.
- リンク情報
- ID情報
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- DOI : 10.1021/acschemneuro.0c00331
- ISSN : 1948-7193
- eISSN : 1948-7193
- PubMed ID : 32790274