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

Oligomers of amyloid-beta (A beta O) are deemed key in synaptotoxicity and amyloid seeding of Alzheimer's disease (AD). However, the heterogeneous and dynamic nature of A beta O and inadequate markers for A beta O subtypes have stymied effective A beta O identification and therapeutic targeting in vivo. We identified an A beta O-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 A beta O-cSNK recognizes similar to 50-60 kDa SDS-resistant soluble A beta assemblages in AD brain and prolongs the lag phase of A beta aggregation in vitro. Acute peripheral infusion of a murine IgG1 anti-A beta O-cSNK in two AD mouse models reduced soluble brain A beta aggregates by 20-30%. Chronic cSNK peptide immunization of APP/PS1 mice engendered an anti-A beta O-csNK IgG1 response without epitope spreading to A beta monomers or fibrils and was accompanied by preservation of global PSD95 expression and improved cued fear memory. Our data indicate that the oligomer subtype A beta O-csNK participates in synaptotoxicity and propagation of A beta aggregation in vitro and in vivo.