Amyloid-β Oligomer Specificity Mediated by the IgM Isotype - Implications for a Specific Protective Mechanism Exerted by Endogenous Auto-Antibodies

被引:53
作者
Lindhagen-Persson, Malin [1 ]
Brannstrom, Kristoffer [1 ]
Vestling, Monika [1 ]
Steinitz, Michael [2 ]
Olofsson, Anders [1 ]
机构
[1] Umea Univ, Dept Med Biochem & Biophys, S-90187 Umea, Sweden
[2] Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Pathol, IL-91010 Jerusalem, Israel
基金
瑞典研究理事会;
关键词
TRAUMATIC BRAIN-INJURY; LONG-TERM POTENTIATION; ALZHEIMERS-DISEASE; A-BETA; PROTEIN-PRECURSOR; MOUSE MODEL; MONOCLONAL-ANTIBODIES; TRANSGENIC MICE; MEMORY LOSS; PEPTIDE;
D O I
10.1371/journal.pone.0013928
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
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.
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页数:9
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