A Rational Structured Epitope Defines a Distinct Subclass of Toxic Amyloid-beta Oligomers

ACS Chem Neurosci. 2018 Jul 18;9(7):1591-1606. doi: 10.1021/acschemneuro.7b00469. Epub 2018 Apr 16.


Oligomers of amyloid-β (AβO) are deemed key in synaptotoxicity and amyloid seeding of Alzheimer's disease (AD). However, the heterogeneous and dynamic nature of AβO and inadequate markers for AβO subtypes have stymied effective AβO identification and therapeutic targeting in vivo. We identified an AβO-subclass epitope defined by differential solvent orientation of the lysine 28 side chain in a constrained loop of serine-asparagine-lysine (cSNK), rarely displayed in molecular dynamics simulations of monomer and fibril ensembles. A mouse monoclonal antibody targeting AβOcSNK recognizes ∼50-60 kDa SDS-resistant soluble Aβ assemblages in AD brain and prolongs the lag phase of Aβ aggregation in vitro. Acute peripheral infusion of a murine IgG1 anti-AβOcSNK in two AD mouse models reduced soluble brain Aβ aggregates by 20-30%. Chronic cSNK peptide immunization of APP/PS1 mice engendered an anti-AβOcSNK IgG1 response without epitope spreading to Aβ monomers or fibrils and was accompanied by preservation of global PSD95 expression and improved cued fear memory. Our data indicate that the oligomer subtype AβOcSNK participates in synaptotoxicity and propagation of Aβ aggregation in vitro and in vivo.

Keywords: Alzheimer’s disease; Amyloid-beta oligomers; epitope; molecular dynamics; neurodegeneration; synaptotoxic.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Alzheimer Disease / psychology
  • Amyloid beta-Peptides / chemistry*
  • Amyloid beta-Peptides / immunology*
  • Animals
  • Brain / immunology
  • Brain / pathology
  • Brain Chemistry
  • Disease Models, Animal
  • Epitopes*
  • Female
  • Humans
  • Male
  • Memory / physiology
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Molecular Dynamics Simulation
  • Plaque, Amyloid / chemistry
  • Plaque, Amyloid / immunology
  • Plaque, Amyloid / pathology
  • Protein Aggregation, Pathological
  • Protein Conformation
  • Protein Multimerization


  • Amyloid beta-Peptides
  • Epitopes