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, pAb2AT-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 pAb2AT-L is neuroprotective against toxic aggregates of Aβ and found that pAb2AT-L protects human iPSC-derived neurons from Aβ42-mediated toxicity at molar ratios as low as 1:100 antibody to Aβ42, 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 pAb2AT-L delays but does not completely inhibit Aβ42 fibrillization at sub-stoichiometric ratios. The ability of pAb2AT-L to inhibit Aβ42 toxicity and aggregation at sub-stoichiometric ratios suggests that pAb2AT-L binds toxic Aβ42 oligomers and does not simply sequester monomeric Aβ42. These results further suggest that toxic oligomers of Aβ42 share significant structural similarities with 2AT-L.