Amyloid-beta peptide-receptor for advanced glycation endproduct interaction elicits neuronal expression of macrophage-colony stimulating factor: A proinflammatory pathway in Alzheimer disease
Amyloid-beta peptide-receptor for advanced glycation endproduct interaction elicits neuronal expression of macrophage-colony stimulating factor: A proinflammatory pathway in Alzheimer disease
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DOI：
10.1073/pnas.94.10.5296
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发表时间：
1997-05-13
影响因子：
11.1
通讯作者：
Schmidt, AM
中科院分区：
文献类型：
--
作者：
Yan, SD;Zhu, HJ;Schmidt, AM
在阿尔茨海默病 (AD) 中，神经元被认为会受到活化小胶质细胞的有害细胞毒性作用。我们证明，淀粉样β肽 (Aβ) 与高级糖基化终产物神经元受体 (RAGE)（一种 Aβ 的细胞表面受体）结合，通过氧化剂敏感的核因子 kappa B 依赖性途径诱导巨噬细胞集落刺激因子 (M-CSF)，AD 大脑显示 A 附近的 M-CSF 神经元表达增加β沉积物，并且在AD患者的脑脊液中，与年龄匹配的对照相比，M-CSF抗原增加了大约5倍（P<0.01），Aβ刺激的神经元释放的M-CSF与其在小胶质细胞上的同源受体c-fms相互作用，从而触发趋化性、细胞增殖、巨噬细胞清道夫受体和载脂蛋白E的表达增加，并提高暴露于A的小胶质细胞的存活率β，与 AD 的病理结果一致，这些数据描绘了由 Aβ 与神经元 RAGE 结合引发的炎症途径。我们认为，由此产生的 M-CSF 有助于 AD 的发病机制，并且脑脊液中的 M-CSF 可能提供一种在 AD 早期监测神经元扰动的方法。
In Alzheimer disease (AD), neurons are thought to be subjected to the deleterious cytotoxic effects of activated microglia, We demonstrate that binding of amyloid-beta peptide (A beta) to neuronal Receptor for Advanced Glycation Endproduct (RAGE), a cell surface receptor for A beta, induces macrophage-colony stimulating factor (M-CSF) by an oxidant sensitive, nuclear factor kappa B-dependent pathway, AD brain shows increased neuronal expression of M-CSF in proximity to A beta deposits, and in cerebrospinal fluid from AD patients there was approximate to 5-fold increased M-CSF antigen (P < 0.01), compared with age-matched controls, M-CSF released by A beta-stimulated neurons interacts with its cognate receptor, c-fms, on microglia, thereby triggering chemotaxis, cell proliferation, increased expression of the macrophage scavenger receptor and apolipoprotein E, and enhanced survival of microglia exposed to A beta, consistent with pathologic findings in AD, These data delineate an inflammatory pathway triggered by engagement of A beta on neuronal RAGE, We suggest that M-CSF, thus generated, contributes to the pathogenesis of AD, and that M-CSF in cerebrospinal fluid might provide a means for monitoring neuronal perturbation at an early stage in AD.