An anti-Aβ (amyloid β) single-chain variable fragment prevents amyloid fibril formation and cytotoxicity by withdrawing Aβ oligomers from the amyloid pathway

Marta Marín-Argany, Geovanny Rivera-Hernández, Joaquim Martí, Sandra Villegas

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28 Citations (Scopus)

Abstract

Aβ (amyloid β) immunotherapy has been revealed as a possible tool in Alzheimer's disease treatment. In contrast with complete antibodies, the administration of scFvs (single-chain variable fragments) produces neither meningoencephalitis nor cerebral haemorrhage. In the present study, the recombinant expression of scFv-h3D6, a derivative of an antibody specific for Aβ oligomers, is presented, as well as the subsequent proof of its capability to recover the toxicity induced by the Aβ1-42 peptide in the SH-SY5Y neuroblastoma cell line. To gain insight into the conformational changes underlying the prevention of Aβ toxicity by this antibody fragment, the conformational landscape of scFv-h3D6 upon temperature perturbation is also described. Heating the native state does not lead to any extent of unfolding, but rather directly to a β-rich intermediate state which initiates an aggregation pathway. This aggregation pathway is not an amyloid fibril pathway, as is that followed by the Aβ peptide, but rather a worm-like fibril pathway which, noticeably, turns out to be nontoxic. On the other hand, this pathway is thermodynamically and kinetically favoured when the scFv-h3D6 and Aβ1-42 oligomers form a complex in native conditions, explaining how the scFvh3D6 withdraws Aβ1-42 oligomers from the amyloid pathway. To our knowledge, this is the first description of a conformational mechanism by which a scFv prevents Aβ-oligomer cytotoxicity. © The Authors Journal compilation © 2011 Biochemical Society.
Original languageEnglish
Pages (from-to)25-34
JournalBiochemical Journal
Volume437
Issue number1
DOIs
Publication statusPublished - 1 Jul 2011

Keywords

  • Aggregation
  • Alzheimer's disease
  • Amyloid β (Aβ) peptide
  • Immunotherapy
  • Single-chain variable fragment (ScFv)
  • Worm-like fibril

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