Donahue John E, Flaherty Stephanie L, Johanson Conrad E, Duncan John A, Silverberg Gerald D, Miller Miles C, Tavares Rosemarie, Yang Wentian, Wu Qian, Sabo Edmond, Hovanesian Virginia, Stopa Edward G
Department of Clinical Neurosciences, Rhode Island Hospital and Brown Medical School, Providence, RI 02903, USA.
Acta Neuropathol. 2006 Oct;112(4):405-15. doi: 10.1007/s00401-006-0115-3. Epub 2006 Jul 25.
The receptor for advanced glycation end products (RAGE) is thought to be a primary transporter of beta-amyloid across the blood-brain barrier (BBB) into the brain from the systemic circulation, while the low-density lipoprotein receptor-related protein (LRP)-1 mediates transport of beta-amyloid out of the brain. To determine whether there are Alzheimer's disease (AD)-related changes in these BBB-associated beta-amyloid receptors, we studied RAGE, LRP-1, and beta-amyloid in human elderly control and AD hippocampi. In control hippocampi, there was robust RAGE immunoreactivity in neurons, whereas microvascular staining was barely detectable. LRP-1 staining, in contrast, was clearly evident within microvessels but only weakly stained neurons. In AD cases, neuronal RAGE immunoreactivity was significantly decreased. An unexpected finding was the strongly positive microvascular RAGE immunoreactivity. No evidence for colocalization of RAGE and beta-amyloid was seen within either microvessels or senile plaques. A reversed pattern was evident for LRP-1 in AD. There was very strong staining for LRP-1 in neurons, with minimal microvascular staining. Unlike RAGE, colocalization of LRP-1 and beta-amyloid was clearly present within senile plaques but not microvessels. Western blot analysis revealed a much higher concentration of RAGE protein in AD hippocampi as compared with controls. Concentration of LRP-1 was increased in AD hippocampi, likely secondary to its colocalization with senile plaques. These data confirm that AD is associated with changes in the relative distribution of RAGE and LRP-1 receptors in human hippocampus. They also suggest that the proportion of amyloid within the brains of AD patients that is derived from the systemic circulation may be significant.
晚期糖基化终末产物受体（RAGE）被认为是β-淀粉样蛋白从体循环穿过血脑屏障（BBB）进入大脑的主要转运体，而低密度脂蛋白受体相关蛋白（LRP）-1介导β-淀粉样蛋白从大脑中转运出去。为了确定这些与血脑屏障相关的β-淀粉样蛋白受体是否存在与阿尔茨海默病（AD）相关的变化，我们研究了人类老年对照和AD海马体中的RAGE、LRP-1和β-淀粉样蛋白。在对照海马体中，神经元中有强烈的RAGE免疫反应性，而微血管染色几乎检测不到。相比之下，LRP-1染色在微血管内明显可见，但神经元染色较弱。在AD病例中，神经元RAGE免疫反应性显著降低。一个意外的发现是微血管RAGE免疫反应性呈强阳性。在微血管或老年斑内均未发现RAGE与β-淀粉样蛋白共定位的证据。AD中LRP-1呈现出相反的模式。神经元中LRP-1染色非常强烈，微血管染色极少。与RAGE不同，LRP-1与β-淀粉样蛋白在老年斑内明显共定位，但在微血管内则没有。蛋白质印迹分析显示，与对照组相比，AD海马体中RAGE蛋白的浓度要高得多。AD海马体中LRP-1的浓度增加，可能是由于其与老年斑共定位所致。这些数据证实，AD与人类海马体中RAGE和LRP-1受体的相对分布变化有关。它们还表明，AD患者大脑中源自体循环的淀粉样蛋白比例可能很大。
