Miller Miles C, Tavares Rosemarie, Johanson Conrad E, Hovanesian Virginia, Donahue John E, Gonzalez Liliana, Silverberg Gerald D, Stopa Edward G
Division of Neuropathology, Department of Pathology, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, 593 Eddy Street (APC 12-219), Providence, RI 02903, USA.
Brain Res. 2008 Sep 16;1230:273-80. doi: 10.1016/j.brainres.2008.06.124. Epub 2008 Jul 14.
Microvascular accumulation and neuronal overproduction of amyloid-beta peptide (Abeta) are pathologic features of Alzheimer's disease (AD). In this study, we examined the receptor for advanced glycation endproducts (RAGE), a multi-ligand receptor found in both neurons and cerebral microvascular endothelia that binds Abeta. RAGE expression was assessed in aged controls (n = 6), patients with early AD-like pathology (n = 6), and severe, Braak V-VI AD (n = 6). Human hippocampi were stained with a specific polyclonal antibody directed against RAGE (Research Diagnostics, Flanders, NJ). Immunoreactivity was localized in both neurons and cerebral endothelial cells. Quantitative image-analyses were performed on grayscale images to assess the total surface area of endothelial RAGE immunoreaction product in cross sections of cerebral microvessels (5-20 microm). Confocal images were acquired for confirmation of RAGE immunoreactivity in both microvessels and neurons by coupling RAGE with CD-31 and neurofilament, respectively. A significant increase in endothelial RAGE immunoreactivity was found in severe Braak V-VI AD patients when compared to aged controls (p < 0.001), and when compared to patients with early AD pathology (p = 0.0125). In addition, a significant increase in endothelial RAGE immunoreactivity was witnessed when comparing aged controls having no reported AD pathology with patients having early AD-like pathology (p = 0.038). Our data suggest that microvascular RAGE levels increase in conjunction with the onset of AD, and continue to increase linearly as a function of AD pathologic severity (p < 0.0001).
淀粉样β肽（Aβ）的微血管积聚和神经元过量生成是阿尔茨海默病（AD）的病理特征。在本研究中，我们检测了晚期糖基化终产物受体（RAGE），这是一种在神经元和脑微血管内皮细胞中均有发现的多配体受体，它能结合Aβ。在老年对照组（n = 6）、具有早期AD样病理特征的患者（n = 6）以及重度Braak V-VI期AD患者（n = 6）中评估了RAGE的表达。用人海马体组织用针对RAGE的特异性多克隆抗体（Research Diagnostics，Flanders，NJ）进行染色。免疫反应性定位于神经元和脑内皮细胞中。对灰度图像进行定量图像分析，以评估脑微血管（5-20微米）横切面中内皮RAGE免疫反应产物的总表面积。通过分别将RAGE与CD-31和神经丝偶联，获取共聚焦图像以确认微血管和神经元中的RAGE免疫反应性。与老年对照组相比（p < 0.001），以及与具有早期AD病理特征的患者相比（p = 0.0125），重度Braak V-VI期AD患者的内皮RAGE免疫反应性显著增加。此外，在比较无AD病理报告的老年对照组与具有早期AD样病理特征的患者时，内皮RAGE免疫反应性也显著增加（p = 0.038）。我们的数据表明，微血管RAGE水平随着AD的发病而增加，并随着AD病理严重程度呈线性持续增加（p < 0.0001）。
