Sasaki N, Toki S, Chowei H, Saito T, Nakano N, Hayashi Y, Takeuchi M, Makita Z
Department of Neuropsychiatry, Sapporo Medical University, South 1, West 16, Chuo-ku, 060-8543, Sapporo, Japan.
Brain Res. 2001 Jan 12;888(2):256-262. doi: 10.1016/s0006-8993(00)03075-4.
Advanced glycation end products (AGE) and the receptor for AGE (RAGE) have been implicated in the chronic complications of diabetes mellitus (DM), and have been reported to play an important role in the pathogenesis of Alzheimer's disease (AD). In this study, we established a polyclonal anti-RAGE antibody, and examined the immunohistochemical localization of amyloid beta protein (Abeta), AGE, and RAGE in neurons and astrocytes from patients with AD and DM. Our anti-RAGE antibody recognized full-length RAGE (50 kd) and N-terminal RAGE (35 kd) in human brain tissue. Abeta-, AGE-, and RAGE-positive granules were identified in the perikaryon of hippocampal neurons (especially from CA3 and CA4) in all subjects. The distribution and staining pattern of these immunopositive granules showed good concordance with each antibody. In AD, most astrocytes contained both AGE-and RAGE-positive granules and their distribution was almost the same. Abeta-positive granules were less common, but Abeta-, AGE-, and RAGE-positive granules were colocalized in one part of a single astrocyte. In DM patients and control cases, AGE-and RAGE-positive astrocytes were very rare. These finding support the hypothesis that glycated Abeta is taken up via RAGE and is degraded through the lysosomal pathway in astrocytes. In addition to the presence of AGE, the process of AGE degradation and receptor-mediated reactions may contribute to neuronal dysfunction and promote the progression of AD.
晚期糖基化终末产物（AGE）及其受体（RAGE）与糖尿病（DM）的慢性并发症有关，并且据报道在阿尔茨海默病（AD）的发病机制中起重要作用。在本研究中，我们制备了一种抗RAGE多克隆抗体，并检测了AD和DM患者神经元和星形胶质细胞中β淀粉样蛋白（Aβ）、AGE和RAGE的免疫组织化学定位。我们的抗RAGE抗体可识别人类脑组织中的全长RAGE（50kd）和N端RAGE（35kd）。在所有受试者海马神经元（尤其是CA3和CA4区）的胞体中均鉴定出Aβ、AGE和RAGE阳性颗粒。这些免疫阳性颗粒的分布和染色模式与每种抗体显示出良好的一致性。在AD中，大多数星形胶质细胞同时含有AGE和RAGE阳性颗粒，且它们的分布几乎相同。Aβ阳性颗粒较少见，但Aβ、AGE和RAGE阳性颗粒在单个星形胶质细胞的一部分中共定位。在DM患者和对照病例中，AGE和RAGE阳性星形胶质细胞非常罕见。这些发现支持了糖化Aβ通过RAGE被摄取并在星形胶质细胞中通过溶酶体途径降解的假说。除了AGE的存在外，AGE降解过程和受体介导的反应可能导致神经元功能障碍并促进AD的进展。
