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

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 AβO^cSNK 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-AβO^cSNK in two AD mouse models reduced soluble brain Aβ aggregates by 20–30%. Chronic cSNK peptide immunization of APP/PS1 mice engendered an anti-AβO^cSNK 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 AβO^cSNK participates in synaptotoxicity and propagation of Aβ aggregation in vitro and in vivo.