Department of Alzheimer's Research, Merck Research Laboratories, West Point, PA 19486, USA. paul
Neurobiol Aging. 2010 Feb;31(2):189-202. doi: 10.1016/j.neurobiolaging.2008.04.003.
Abeta-derived diffusible ligands (ADDLs) are abundant in AD brain, bind to hippocampal neurons and induce deficits in rodent cognition. To further investigate ADDL binding to neurons and identify antibodies that block this association, a panel of anti-Abeta and anti-ADDL antibodies was characterized for their ability to immuno-detect neuronally bound ADDLs and attenuate the binding of ADDLs to neurons. The results showed that anti-Abeta and anti-ADDL antibodies were able to abate ADDLs binding to hippocampal neurons, but to different degrees. Quantitative assessment of binding showed that one antibody, ACU-954 was markedly more effective at blocking ADDL binding than other antibodies assessed. ACU-954 was also found to block ADDL binding to hippocampal slice cultures, attenuate the ADDL-induced loss of dendritic spines and detect "natural ADDLs" in human AD tissue. These results demonstrated that antibodies that bind to and block ADDL binding to neurons can be identified, although their efficacy is conformationally specific since it is not readily apparent or predictable based on the core linear epitope or affinity for monomeric Abeta.
β淀粉样肽衍生的可扩散配体（ADDLs）在 AD 脑中含量丰富，与海马神经元结合，并导致啮齿动物认知功能缺陷。为了进一步研究 ADDL 与神经元的结合，并鉴定出能阻断这种结合的抗体，我们对一组抗β淀粉样肽和抗 ADDL 抗体进行了鉴定，以评估它们识别神经元结合 ADDLs 的能力，并减弱 ADDLs 与神经元的结合。结果表明，抗β淀粉样肽和抗 ADDL 抗体能够减弱 ADDLs 与海马神经元的结合，但程度不同。结合的定量评估表明，一种名为 ACU-954 的抗体在阻断 ADDL 结合方面比其他评估的抗体更有效。ACU-954 还被发现可以阻断 ADDL 与海马切片培养物的结合，减弱 ADDL 诱导的树突棘丢失，并检测人类 AD 组织中的“天然 ADDLs”。这些结果表明，可以鉴定出与神经元结合并阻断 ADDL 结合的抗体，尽管它们的功效具有构象特异性，因为基于核心线性表位或对单体 Abeta 的亲和力，这种特异性不易察觉或预测。
