Aβ(M1–40) and wild-type Aβ40 self-assemble into oligomers with distinct quaternary structures

Jacob L. Bouchard, Taylor C. Davey, Todd M. Doran

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Amyloid-β oligomers (AβOs) self-assemble into polymorphic species with diverse biological activities that are implicated causally to Alzheimer’s disease (AD). Synaptotoxicity of AβO species is dependent on their quaternary structure, however, low-abundance and environmental sensitivity of AβOs in vivo have impeded a thorough assessment of structure–function relationships. We developed a simple biochemical assay to quantify the relative abundance and morphology of cross-linked AβOs. We compared oligomers derived from synthetic Aβ40 (wild-type (WT) Aβ40) and a recombinant source, called Aβ(M1–40). Both peptides assemble into oligomers with common sizes and morphology, however, the predominant quaternary structures of Aβ(M1–40) oligomeric states were more diverse in terms of dispersity and morphology. We identified self-assembly conditions that stabilize high-molecular weight oligomers of Aβ(M1–40) with apparent molecular weights greater than 36 kDa. Given that mixtures of AβOs derived from both peptides have been shown to be potent neurotoxins that disrupt long-term potentiation, we anticipate that the diverse quaternary structures reported for Aβ(M1–40) oligomers using the assays reported here will facilitate research efforts aimed at isolating and identifying common toxic species that contribute to synaptic dysfunction.

Original languageEnglish (US)
Article number2242
JournalMolecules
Volume24
Issue number12
DOIs
StatePublished - Jun 15 2019

Bibliographical note

Funding Information:
Funding: This research was funded by the University of Minnesota Twin Cities.

Publisher Copyright:
© 2019 by the authors.

Keywords

  • Alzheimer’s disease
  • Amyloid-β
  • Conformation
  • High-molecular weight (HMW) oligomers
  • Low-molecular weight (LMW) oligomers
  • Morphology
  • Oligomers
  • PICUP
  • Quaternary structure
  • Recombinant Aβ

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