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

Abstract

Anti-A{beta} antibodies are important tools for identifying structural features of aggregates of the A{beta} peptide and are used in many aspects of Alzheimers disease (AD) research. Our laboratory recently reported the generation of a polyclonal antibody, pAb2AT-L, that is moderately selective for oligomeric A{beta} over monomeric and fibrillar A{beta} and recognizes the diffuse peripheries of A{beta} plaques in AD brain tissue but does not recognize the dense fibrillar plaque cores. This antibody was generated against 2AT-L, a structurally defined A{beta} oligomer mimic composed of three A{beta}-derived {beta}-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 A{beta} and found that pAb2AT-L protects human iPSC-derived neurons from A{beta}42-mediated toxicity at molar ratios as low as 1:100 antibody to A{beta}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 A{beta}. ThT and TEM studies indicate that pAb2AT-L delays but does not completely inhibit A{beta}42 fibrillization at sub-stoichiometric ratios. The ability of pAb2AT-L to inhibit A{beta}42 toxicity and aggregation at sub-stoichiometric ratios suggests that pAb2AT-L binds toxic A{beta}42 oligomers and does not simply sequester monomeric A{beta}42. These results further suggest that toxic oligomers of A{beta}42 share significant structural similarities with 2AT-L. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/654602v1_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@d97c84org.highwire.dtl.DTLVardef@7dd416org.highwire.dtl.DTLVardef@ef072borg.highwire.dtl.DTLVardef@bfd614_HPS_FORMAT_FIGEXP M_FIG C_FIG