Figure 4. OMAB inhibits the cytotoxicity of Ab(1–42) in a substoichiometric ratio. OMAB was incubated with SH-SY5Y cells in the presence or absence of Ab(1–42). After 48 hours, cell viability was detected using resazurin. # = p,0.001 compared to control cells and * = p,0.001 compared to cells treated with only Ab(1–42). doi:10.1371/journal.pone.0013928.g004 evidence implicates soluble Ab oligomers as highly promising therapeutic targets. There are different approaches to the targeting of soluble Ab oligomers, one approach being immunization. Promising results have been obtained with both active and passive immunization in AD mice [3,4,5,6,7,8]. However, active vaccination performed in human AD patients has, to date, resulted in only moderate clinical improvements and, in a small number of patients, been associated with a pathological auto-immune T-cell response resulting in encephalitis [38]. In this respect passive vaccination may provide a safer alternative. Administration of an anti-Ab antibody can reverse spatial memory deficits in AD mice after only a few days of treatment without affecting the total burden of deposited Ab [6,39]. These findings suggest that neuronal death represents a late stage in the pathology of AD, and that earlier events in the disease may impair neuronal function without neurodegeneration. If a selective scavenger of Ab oligomers could be administered at an early stage of the disease, AD- related brain damage could potentially be reduced. In a recent publication, monomeric Ab was shown to have a neuroprotective effect by preventing NMDA-induced exitotoxicity [10]. This finding is in accordance with previous results showing that Ab levels increase following brain injury [40,41,42]. This finding implies that Ab might have an important physiological role in vivo, a fact that should be considered when designing therapeutic strategies. It is important that the antibodies used in AD therapeutics have selective properties, and avoid binding both monomeric Ab and native APP. Several different oligomer-specific IgG antibodies have been created to selectively target the specific fold that only Ab oligomers are believed to possess [12,13,14,15]. To avoid the difficulty of creating an antibody that recognizes a specific conformational architecture only present within the oligomers, we have chosen a different approach. Our technique is based on the rationale that all oligomers are multivalent, i.e. they potentially expose a number of identical epitopes. An efficient oligomer-specific receptor should, therefore be multivalent. However, to facilitate a dynamic screening for oligomers also in complex solutions in high excess of monomeric species, it is equally important to have a fast on- and off-rate at each single binding site. Targeting Ab Oligomers Figure 5. Human IgM auto-antibodies specifically detect Ab oligomers. A sample containing different oligomeric species of Ab(1– 42) was separated by SEC (-). Fractions, collected throughout the SEC, were tested in an indirect ELISA for reactivity with (A) L11.3 (---) or (B) plasma from eight different human donors (---). Before adding L11.3 or plasma, the ELISA plate was coated with an anti-human IgM antibody to ensure that only IgM auto-antibodies were allowed to react with the Ab species. The level of endogenous anti-Ab antibodies is low in the plasma and to ensure a measurable response 5X more total Ab was applied on the SEC column which explains the different elution profiles. doi:10.1371/journal.pone.0013928.g005 All species of Ab exposing the target sequence will hence have the same ability to bind but, as a result of the avidity effect, the dissociation rate will be strongly reduced in oligomeric assemblies. Thus, the low affinity of each single interaction is compensated by a high avidity, the product of all single interactions. In other words the probability that all antigen-antibody interactions will dissociate simultaneously is exceedingly small therefore, if one interaction is dissociated, the others will remain associated, thus enhancing the probability that those dissociated will re-associate. The multivalent IgM architecture fulfils the criteria of an effective oligomer receptor. In the current work, we characterized the oligomer specificity of OMAB, a newly designed monoclonal PLoS ONE | www.plosone.org 6 November 2010 | Volume 5 | Issue 11 | e13928