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摘要
Background: Alzheimers disease (AD) has been strongly linked to an anomalous self-assembly of the amyloid-beta peptide (A beta). The correlation between clinical symptoms of AD and A beta depositions is, however, weak. Instead small and soluble A beta oligomers are suggested to exert the major pathological effects. In strong support of this notion, immunological targeting of A beta oligomers in AD mice-models shows that memory impairments can be restored without affecting the total burden of A beta deposits. Consequently a specific immunological targeting of A beta oligomers is of high therapeutic interest.
Methodology/Principal Findings: Previously the generation of conformational-dependent oligomer specific anti-A beta antibodies has been described. However, to avoid the difficult task of identifying a molecular architecture only present on oligomers, we have focused on a more general approach based on the hypothesis that all oligomers expose multiple identical epitopes and therefore would have an increased binding to a multivalent receptor. Using the polyvalent IgM immunoglobulin we have developed a monoclonal anti-A beta antibody (OMAB). OMAB only demonstrates a weak interaction with A beta monomers and dimers having fast on and off-rate kinetics. However, as an effect of avidity, its interaction with A beta-oligomers results in a strong complex with an exceptionally slow off-rate. Through this mechanism a selectivity towards A beta oligomers is acquired and OMAB fully inhibits the cytotoxic effect exerted by A beta(1-42) at highly substoichiometric ratios. Anti-A beta auto-antibodies of IgM isotype are frequently present in the sera of humans. Through a screen of endogenous anti-A beta IgM auto-antibodies from a group of healthy individuals we show that all displays a preference for oligomeric A beta.
Conclusions/Significance: Taken together we provide a simple and general mechanism for targeting of oligomers without the requirement of conformational-dependent epitopes. In addition, our results suggest that IgM anti-A beta auto-antibodies may exert a more specific protective mechanism in vivo than previously anticipated.
- 出版日期2010-11-10
