Stabilization and Characterization of Cytotoxic Aβ 40 Oligomers Isolated from an Aggregation Reaction in the Presence of Zinc Ions

Benedetta Mannini, Johnny Habchi, Sean Chia, Francesco S. Ruggeri, Michele Perni, Tuomas P.J. Knowles, Christopher M. Dobson, Michele Vendruscolo*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

47 Citations (Scopus)

Abstract

Small oligomers formed during the aggregation of certain peptides and proteins are highly cytotoxic in numerous neurodegenerative disorders. Because of their transient nature and conformational heterogeneity, however, the structural and biological features of these oligomers are still poorly understood. Here, we describe a method of generating stable oligomers formed by the Alzheimer's Aβ40 peptide by carrying out an aggregation reaction in the presence of zinc ions. The resulting oligomers are amenable to detailed biophysical and biological characterization, which reveals a homogeneous population with small size, high cross-β sheet structure content, and extended hydrophobic surface patches. We also show that these oligomers decrease the viability of neuroblastoma cells and impair the motility of C. elegans. The availability of these oligomers offers novel opportunities for studying the mechanisms of Aβ 40 toxicity in vitro and in cellular and animal models of Alzheimer's disease.
Original languageEnglish
Pages (from-to)2959-2971
Number of pages13
JournalACS Chemical Neuroscience
Volume9
Issue number12
DOIs
Publication statusPublished - 19 Dec 2018
Externally publishedYes

Keywords

  • Alzheimer's disease
  • amyloid
  • antiparallel oligomer
  • metal ions
  • OC-positive aggregates
  • Protein oligomer aggregates

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