title: Self-assembly pathways of E22Δ-type amyloid β peptide mutants generated from non-aggregative O-acyl isopeptide precursors.
abstract: The recently identified E22Δ-type amyloid β peptide (Aβ) mutants are reported to favor oligomerization over fibrillization and to exhibit more-potent synaptotoxicity than does wild-type (WT) Aβ. Aβ(E22Δ) mutants can thus be expected to serve as tools for clarifying the impact of Aβ oligomers in Alzheimer's disease (or Alzheimer's-type dementia). However, the biochemical and biophysical properties of Aβ(E22Δ) have not been conclusively determined. Here, we evaluated the self-assembly pathways of Aβ(E22Δ) mutants generated from water-soluble, non-aggregative O-acyl isopeptide precursors. Circular dichroism spectroscopy, Western blot analysis, and thioflavin-T fluorescence intensity and cellular toxicity assays suggest that the self-assembly pathways of Aβ(E22Δ) differed from those of Aβ(WT). Aβ1-40(E22Δ) underwent a rapid random coil→β-sheet conformational change in its monomeric or low-molecular-weight oligomeric states, whereas Aβ1-40(WT) self-assembled gradually without losing its propensity to form random coil structures. The Aβ1-42(E22Δ) monomer formed β-sheet-rich oligomers more rapidly than did Aβ1-42(WT). Additionally, the Aβ1-42(E22Δ) oligomers appear to differ from Aβ1-42(WT) oligomers in size, shape, or both. These results should provide new insights into the functions of Aβ(E22Δ) mutants.
authors: Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Kyoto 607-8412, Japan. ysohma@mb.kyoto-phu.ac.jp
authors: Youhei
authors: Y
authors: Sohma
authors: Hui
authors: H
authors: Wang
authors: Atsuhiko
authors: A
authors: Taniguchi
authors: Yuta
authors: Y
authors: Hirayama
authors: Taeko
authors: T
authors: Kakizawa
authors: Moe
authors: M
authors: Yamasaki
authors: Hidehito
authors: H
authors: Mukai
authors: Yoshiaki
authors: Y
authors: Kiso