Piechotta Anke, Parthier Christoph, Kleinschmidt Martin, Gnoth Kathrin, Pillot Thierry, Lues Inge, Demuth Hans-Ulrich, Schilling Stephan, Rahfeld Jens-Ulrich, Stubbs Milton T
Probiodrug AG, Weinbergweg 22, 06120 Halle (Saale), Germany; Institute of Biotechnology, Martin Luther University, 06108 Halle-Wittenberg, Germany; Department of Molecular Drug Biochemistry and Therapy, Fraunhofer Institute for Cell Therapy and Immunology, Weinbergweg 22, 06120 Halle, Germany.
Institute of Biotechnology, Martin Luther University, 06108 Halle-Wittenberg, Germany.
J Biol Chem. 2017 Jul 28;292(30):12713-12724. doi: 10.1074/jbc.M117.777839. Epub 2017 Jun 16.
Alzheimer disease is associated with deposition of the amyloidogenic peptide Aβ in the brain. Passive immunization using Aβ-specific antibodies has been demonstrated to reduce amyloid deposition both and Because N-terminally truncated pyroglutamate (pE)-modified Aβ species (Aβ) exhibit enhanced aggregation potential and propensity to form toxic oligomers, they represent particularly attractive targets for antibody therapy. Here we present three separate monoclonal antibodies that specifically recognize Aβ with affinities of 1-10 nm and inhibit Aβ fibril formation application of one of these resulted in improved memory in Aβ oligomer-treated mice. Crystal structures of F-Aβ complexes revealed two distinct binding modes for the peptide. Juxtaposition of pyroglutamate pE3 and the F4 side chain (the "pEF head") confers a pronounced bulky hydrophobic nature to the Aβ N terminus that might explain the enhanced aggregation properties of the modified peptide. The deep burial of the pEF head by two of the antibodies explains their high target specificity and low cross-reactivity, making them promising candidates for the development of clinical antibodies.
阿尔茨海默病与淀粉样蛋白生成肽Aβ在大脑中的沉积有关。使用Aβ特异性抗体进行被动免疫已被证明可减少淀粉样蛋白沉积，且由于N端截短的焦谷氨酸（pE）修饰的Aβ物种（Aβ）表现出增强的聚集潜力和形成有毒寡聚体的倾向，它们是抗体治疗特别有吸引力的靶点。在此，我们展示了三种分别特异性识别Aβ的单克隆抗体，其亲和力为1 - 10 nM，并抑制Aβ纤维形成，应用其中一种抗体可改善Aβ寡聚体处理小鼠的记忆力。F - Aβ复合物的晶体结构揭示了该肽的两种不同结合模式。焦谷氨酸pE3与F4侧链的并置（“pEF头”）赋予Aβ N端明显的大体积疏水性质，这可能解释了修饰肽增强的聚集特性。两种抗体对pEF头的深度掩埋解释了它们的高靶点特异性和低交叉反应性，使其成为开发临床抗体的有希望的候选者。
