Induction of Neuronal Death by Microglial AGE-Albumin: Implications for Alzheimer’s Disease

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.晚期糖基化终末产物（Advanced glycation end products，AGEs）长期以来被认为是可促进神经元死亡、参与阿尔茨海默病（Alzheimer’s disease，AD）等神经退行性疾病发生发展的强效分子。本研究证实，人类阿尔茨海默病脑内丰度最高的晚期糖基化终末产物修饰白蛋白（AGE-albumin）可在活化小胶质细胞中合成并分泌至细胞外间隙。人类小胶质细胞中晚期糖基化终末产物修饰白蛋白的合成速率，可因β淀粉样蛋白（amyloid-β，Aβ）暴露与氧化应激而显著升高。外源性晚期糖基化终末产物修饰白蛋白可上调晚期糖基化终末产物受体（receptor for AGE，RAGE）的表达，增强钙内流，最终诱导人类原代神经元凋亡。动物实验显示，可溶性晚期糖基化终末产物受体（soluble RAGE，sRAGE）、吡多胺（pyridoxamine）与ALT-711均可抑制大鼠脑内β淀粉样蛋白诱导的神经元死亡。综上，本研究结果揭示了一条全新的致病机制：小胶质细胞可通过合成并分泌晚期糖基化终末产物修饰白蛋白，促进神经元死亡，进而可能参与阿尔茨海默病等神经退行性疾病的发生发展。