Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
PLoS One. 2010 Nov 10;5(11):e13928. doi: 10.1371/journal.pone.0013928.
Alzheimers disease (AD) has been strongly linked to an anomalous self-assembly of the amyloid-β peptide (Aβ). The correlation between clinical symptoms of AD and Aβ depositions is, however, weak. Instead small and soluble Aβ oligomers are suggested to exert the major pathological effects. In strong support of this notion, immunological targeting of Aβ oligomers in AD mice-models shows that memory impairments can be restored without affecting the total burden of Aβ deposits. Consequently a specific immunological targeting of Aβ oligomers is of high therapeutic interest.
METHODOLOGY/PRINCIPAL FINDINGS: Previously the generation of conformational-dependent oligomer specific anti-Aβ 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-Aβ antibody (OMAB). OMAB only demonstrates a weak interaction with Aβ monomers and dimers having fast on and off-rate kinetics. However, as an effect of avidity, its interaction with Aβ-oligomers results in a strong complex with an exceptionally slow off-rate. Through this mechanism a selectivity towards Aβ oligomers is acquired and OMAB fully inhibits the cytotoxic effect exerted by Aβ(1-42) at highly substoichiometric ratios. Anti-Aβ auto-antibodies of IgM isotype are frequently present in the sera of humans. Through a screen of endogenous anti-Aβ IgM auto-antibodies from a group of healthy individuals we show that all displays a preference for oligomeric Aβ.
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-Aβ auto-antibodies may exert a more specific protective mechanism in vivo than previously anticipated.
阿尔茨海默病（AD）与淀粉样β肽（Aβ）的异常自组装密切相关。然而，AD 的临床症状与 Aβ 沉积之间的相关性很弱。相反，小而可溶性的 Aβ 寡聚体被认为发挥主要的病理作用。这一观点得到了强有力的支持，即在 AD 小鼠模型中针对 Aβ 寡聚体的免疫靶向表明，在不影响 Aβ 沉积总量的情况下，可以恢复记忆障碍。因此，针对 Aβ 寡聚体的特异性免疫靶向具有很高的治疗意义。
方法/主要发现：以前已经描述了针对构象依赖性寡聚体特异性抗 Aβ 抗体的产生。然而，为了避免识别仅存在于寡聚体上的分子结构这一艰巨任务，我们专注于一种更通用的方法，基于这样的假设，即所有寡聚体都暴露多个相同的表位，因此会增加与多价受体的结合。我们使用多价 IgM 免疫球蛋白开发了一种单克隆抗 Aβ 抗体（OMAB）。OMAB 仅与 Aβ 单体和二聚体表现出较弱的相互作用，具有快速的 ON 和 OFF 速率动力学。然而，由于亲和力的作用，其与 Aβ-寡聚体的相互作用导致与异常缓慢的 OFF 速率形成强复合物。通过这种机制，获得了对 Aβ 寡聚体的选择性，并且 OMAB 完全抑制了 Aβ（1-42）在高度亚化学计量比下产生的细胞毒性作用。IgM 同种型的抗 Aβ 自身抗体经常存在于人类血清中。通过对一组健康个体的内源性抗 Aβ IgM 自身抗体进行筛选，我们发现所有抗体都优先与寡聚 Aβ 结合。
结论/意义：总之，我们提供了一种简单而通用的针对寡聚体的靶向机制，而无需构象依赖性表位。此外，我们的结果表明，与之前预期的相比，IgM 抗 Aβ 自身抗体在体内可能发挥更特异的保护机制。
