Department of Biological Sciences, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
Biochem Biophys Res Commun. 2013 Sep 20;439(2):252-7. doi: 10.1016/j.bbrc.2013.08.047. Epub 2013 Aug 23.
Amyloid-β (Aβ) peptide is central to the development of brain pathology in Alzheimer disease (AD) patients. Association with receptors for advanced glycation end-products (RAGE) enables the transport of Aβ peptide from circulating blood to human brain, and also causes the activation of the NF-κB signaling pathway. Here we show that two β-strands of RAGE participate in the interaction with Aβ peptide. Serial deletion analysis of the RAGE V domain indicates that the third and eighth β-strands are required for interaction with Aβ peptide. Site-directed mutagenesis of amino acids located in the third and eighth β-strands abolish the interaction of RAGE with Aβ peptide. Wild-type RAGE activates the NF-κB signaling pathway in response to Aβ peptide treatment, while a RAGE mutant defective in Aβ binding does not. Furthermore, use of peptide for the third β-strand or a RAGE monoclonal antibody that targets the RAGE-Aβ interaction interface inhibited transport of the Aβ peptide across the blood brain barrier in a mice model. These results provide information crucial to the development of RAGE-derived therapeutic reagents for Alzheimer disease.
淀粉样蛋白-β（Aβ）肽是阿尔茨海默病（AD）患者大脑病理学发展的核心。与晚期糖基化终产物受体（RAGE）的结合使 Aβ肽能够从循环血液中转运到人类大脑，并导致 NF-κB 信号通路的激活。在这里，我们表明 RAGE 的两个β-链参与了与 Aβ肽的相互作用。RAGE V 结构域的串联缺失分析表明，第三和第八个β-链是与 Aβ肽相互作用所必需的。位于第三和第八个β-链中的氨基酸的定点突变消除了 RAGE 与 Aβ肽的相互作用。野生型 RAGE 对 Aβ肽处理会激活 NF-κB 信号通路，而 Aβ结合缺陷的 RAGE 突变体则不会。此外，使用针对第三β-链的肽或针对 RAGE-Aβ相互作用界面的 RAGE 单克隆抗体可抑制 Aβ肽在小鼠模型中穿过血脑屏障的转运。这些结果为开发用于治疗阿尔茨海默病的 RAGE 衍生治疗试剂提供了至关重要的信息。
