内源性晚期糖基化终产物分泌受体抑制小鼠脑内淀粉样β1-42 的摄取。

Endogenous secretory receptor for advanced glycation end-products inhibits amyloid-β1-42 uptake into mouse brain.

机构信息

Department of Biochemistry and Molecular Vascular Biology, Kanazawa University, Graduate School of Medical Science, Kanazawa, Japan.

出版信息

J Alzheimers Dis. 2012;28(3):709-20. doi: 10.3233/JAD-2011-110776.

DOI:10.3233/JAD-2011-110776

PMID:22064071

Abstract

The cell-surface receptor for advanced glycation end-products (RAGE) has been implicated in the development of diabetic vascular complications and Alzheimer's disease. RAGE has been considered to be involved in amyloid-β1-42 (Aβ1-42) uptake into brain. In the present study, we demonstrate that endogenous secretory RAGE (esRAGE), a decoy form of RAGE generated by alternative RNA processing, is able to inhibit Aβ1-42 influx into mouse brain. Surface plasmon resonance and competitive binding assays revealed that human Aβ1-42 interacted with human esRAGE within the immunoglobulin V type region. We next examined the uptake and distribution of 125I-labeled human Aβ1-42 in various organs and body fluids of newly created mice overexpressing human esRAGE as well as RAGE-null and wild-type (WT) mice. The transition of the 125I-labeled Aβ1-42 from circulation to brain parenchyma peaked at 30 min after the injection into WT mice, but this was significantly blunted in esRAGE-overexpressing and RAGE-null mice. Significant reduction in 125I-labeled Aβ1-42-derived photo-stimulated luminescence were marked in ventricles, cerebral cortex, hippocampus, especially CA1 and CA3 regions, putamen, and thalamus. The results thus suggest the potential of esRAGE in protection against the development of Alzheimer's disease.

摘要

晚期糖基化终产物（RAGE）的细胞表面受体与糖尿病血管并发症和阿尔茨海默病的发生有关。RAGE 被认为参与了淀粉样β1-42（Aβ1-42）进入大脑。在本研究中，我们证明了内源性分泌型 RAGE（esRAGE），一种通过 RNA 剪接产生的 RAGE 诱饵形式，能够抑制 Aβ1-42 进入小鼠大脑。表面等离子体共振和竞争结合实验表明，人 Aβ1-42 与人 esRAGE 在免疫球蛋白 V 型区域内相互作用。我们接下来研究了在过表达人 esRAGE 以及 RAGE 缺失和野生型（WT）小鼠中，125I 标记的人 Aβ1-42 在各种器官和体液中的摄取和分布。125I 标记的 Aβ1-42 从循环系统向脑实质的转移在 WT 小鼠中注射后 30 分钟达到峰值，但在 esRAGE 过表达和 RAGE 缺失小鼠中明显减弱。在脑室、大脑皮层、海马体，特别是 CA1 和 CA3 区、纹状体和丘脑，125I 标记的 Aβ1-42 衍生的光刺激发光显著减少。结果表明 esRAGE 具有预防阿尔茨海默病发生的潜力。