Identification of physiological and toxic conformations in Aβ42 aggregates

Yuichi Masuda, Satoko Uemura, Ryutaro Ohashi, Azusa Nakanishi, K. Takegoshi, Takahiko Shimizu, Takuji Shirasawa, Kazuhiro Irie

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

Aggregation of the 42-residue amyloid β-protein (Aβ42) plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Despite numerous structural studies on Aβ aggregates, the relationship between tertiary structure and toxicity remains unclear. Our proline scanning and solid-state NMR studies suggested that aggregates both of wild-type Aβ42 and of E22K-Aβ42 (one of the mutants related to cerebral amyloid angiopathy) contain two conformers: a major one with a turn at positions 25 and 26, and a minor one with a turn at positions 22 and 23. To identify the toxic conformer, the derivative Aβ42-lactam(22K-23E), in which the side chains at positions 22 and 23 were covalently linked, was synthesized as a minor conformer surrogate, along with Aβ42-lactam(25K-26E) as a major conformer surrogate. The Aβ42-lactam(22K-23E) showed stronger aggregation, neurotoxicity, radical generation, and oligomerization than wild-type Aβ42, whereas in Aβ42-lactam(25K-26E) were weak. The transition from the physiological conformation with a turn at positions 25 and 26 to the toxic conformation with a turn at positions 22 and 23 might be a key event in the pathogenesis of AD.

Original languageEnglish
Pages (from-to)287-295
Number of pages9
JournalChemBioChem
Volume10
Issue number2
DOIs
Publication statusPublished - 2009 Jan 26

Keywords

  • Alzheimer's disease
  • Amyloid
  • Protein structures
  • Radicals
  • Solid-state NMR

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

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  • Cite this

    Masuda, Y., Uemura, S., Ohashi, R., Nakanishi, A., Takegoshi, K., Shimizu, T., Shirasawa, T., & Irie, K. (2009). Identification of physiological and toxic conformations in Aβ42 aggregates. ChemBioChem, 10(2), 287-295. https://doi.org/10.1002/cbic.200800411