P4–289: Normal healthy donors possess plasma IgG reactive to a neutralizing epitope for toxic and amyloid‐seeding beta‐amyloid oligomers

Oligomers of amyloid-β (Aβ) peptide are implicated in Alzheimer's disease (AD) synaptic dysfunction, tau phosphorylation and neurofibrillary tangle deposition, neuronal cell death and regional spread of Aβ amyloidosis in the brain. We have identified an immunological epitope unique to Aβ oligomers comprising the structurally constrained tripeptide cyclized serine-asparagine-lysine (cSNK). We have reported that the mouse cSNK-specific IgG1 monoclonal antibody 5E3 recognizes synthetic and AD brain-derived Aβ oligomers of 45–55 kDa, and blocks neurotoxicity and Aβ(1–42) oligomer growth in vitro 1. The in vivo activity of 5E3 on neurotoxicity/synaptotoxicity was evaluated by novel object recognition (NOR) test performed in C57BL/6 wild-type mice intraventricularly co-injected 2 hours earlier with antibody combined with synthetic Aβ(1–42) oligomers 2. P urified IgG from young healthy donors were assayed for cSNK and synthetic Aβ(1–42) oligomers using Biacore TM 1 and MagPlex TM5 immunoassays 1,3. Preincubation with the monoclonal 5E3, but not control IgG1, effectively abrogated the acute NOR deficit induced by injection of A b(1–42) oligomers (p<0.01); no NOR deficit was observed on infusion of 5E3 antibody alone. MagPlex TM and Biacore TM immunoassays revealed cSNK IgG in young healthy donors, which were strongly correlated (Pearson test p<0.005). Biacore TM revealed strong correlation of IgG binding to cSNK peptide and A β(1–42) oligomers (Pearson test p<0.001). cSNK IgG was primarily IgG1 subclass, ∼ 500 nM affinity for A β(1–42) oligomers. The data are consistent with the cSNK defining a “neutralizing epitope” for those Aβ oligomers triggering neurotoxicity/synaptotoxicity and oligomer propagation. Natural or engineered antibodies against cSNK may have efficacy as an AD passive immunotherapy, and cSNK as a prophylactic vaccine target for populations at high-risk for AD. 1) Silverman et al. Alz Demen 2012; 8 suppl.04–06–03. 2) Balducci et al. Proc Natl Acad Sci U S A. 2010; 107:2295–300. 3) Toth et al Alz Demen, 2012; 8 suppl. P1–228.

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