Center for Genomics and Proteomics, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon, Korea.
PLoS One. 2012;7(5):e37917. doi: 10.1371/journal.pone.0037917. Epub 2012 May 25.
Advanced glycation end products (AGEs) have long been considered as potent molecules promoting neuronal cell death and contributing to neurodegenerative disorders such as Alzheimer's disease (AD). In this study, we demonstrate that AGE-albumin, the most abundant AGE product in human AD brains, is synthesized in activated microglial cells and secreted into the extracellular space. The rate of AGE-albumin synthesis in human microglial cells is markedly increased by amyloid-β exposure and oxidative stress. Exogenous AGE-albumin upregulates the receptor protein for AGE (RAGE) and augments calcium influx, leading to apoptosis of human primary neurons. In animal experiments, soluble RAGE (sRAGE), pyridoxamine or ALT-711 prevented Aβ-induced neuronal death in rat brains. Collectively, these results provide evidence for a new mechanism by which microglial cells promote death of neuronal cells through synthesis and secretion of AGE-albumin, thereby likely contributing to neurodegenerative diseases such as AD.
糖基化终产物（AGEs）长期以来被认为是促进神经元细胞死亡的有效分子，并导致阿尔茨海默病（AD）等神经退行性疾病的发生。在这项研究中，我们证明 AGE-白蛋白（AGE 产物中在人 AD 脑中含量最丰富的一种）是由活化的小胶质细胞合成并分泌到细胞外间隙的。人小胶质细胞中 AGE-白蛋白的合成速率在受到淀粉样蛋白-β（Aβ）和氧化应激的刺激后显著增加。外源性 AGE-白蛋白上调 AGE 的受体蛋白（RAGE）并增加钙内流，导致人原代神经元凋亡。在动物实验中，可溶性 RAGE（sRAGE）、吡哆胺或 ALT-711 可预防 Aβ 诱导的大鼠大脑中神经元死亡。总之，这些结果为小胶质细胞通过合成和分泌 AGE-白蛋白促进神经元细胞死亡的新机制提供了证据，这可能导致 AD 等神经退行性疾病的发生。
