Antibodies raised against a structurally defined Aβ oligomer mimic protect human iPSC neurons from Aβ toxicity at sub-stoichiometric concentrations

Anti-Aβ antibodies are important tools for identifying structural features of aggregates of the Aβ peptide and are used in many aspects of Alzheimer’s disease (AD) research. Our laboratory recently reported the generation of a polyclonal antibody, pAb _2AT-L , that is moderately selective for oligomeric Aβ over monomeric and fibrillar Aβ and recognizes the diffuse peripheries of Aβ plaques in AD brain tissue but does not recognize the dense fibrillar plaque cores. This antibody was generated against 2AT-L, a structurally defined Aβ oligomer mimic composed of three Aβ-derived β-hairpins arranged in a triangular fashion and covalently stabilized with three disulfide bonds. In the current study, we set out to determine if pAb _2AT-L is neuroprotective against toxic aggregates of Aβ and found that pAb _2AT-L protects human iPSC-derived neurons from Aβ ₄₂ -mediated toxicity at molar ratios as low as 1:100 antibody to Aβ ₄₂ , with a ratio of 1:25 almost completely rescuing cell viability. Few other antibodies have been reported to exhibit neuroprotective effects at such low ratios of antibody to Aβ. ThT and TEM studies indicate that pAb _2AT-L delays but does not completely inhibit Aβ ₄₂ fibrillization at sub-stoichiometric ratios. The ability of pAb _2AT-L to inhibit Aβ ₄₂ toxicity and aggregation at sub-stoichiometric ratios suggests that pAb _2AT-L binds toxic Aβ ₄₂ oligomers and does not simply sequester monomeric Aβ ₄₂ . These results further suggest that toxic oligomers of Aβ ₄₂ share significant structural similarities with 2AT-L.