Sphingomyelin accumulation provides a favorable milieu for GM1 ganglioside-induced assembly of amyloid β-protein
Sphingomyelin accumulation provides a favorable milieu for GM1 ganglioside-induced assembly of amyloid β-protein
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DOI：
10.1016/j.neulet.2010.06.080
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发表时间：
2010-09
影响因子：
2.5
通讯作者：
K. Yuyama;K. Yanagisawa
中科院分区：
文献类型：
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作者：
K. Yuyama;K. Yanagisawa
淀粉样β蛋白组装成纤维是阿尔茨海默病（AD）的初始事件。以往的研究表明，神经节苷脂结合的淀粉样β蛋白（Aβ），GAβ，是阿尔茨海默病（AD）脑内淀粉样蛋白的内源性种子，GAβ产生于膜微区，包括胆固醇，鞘磷脂（SM）和GM1神经节苷脂。在这项研究中，我们发现，GAβ依赖的淀粉样蛋白的生成被加速的PC 12细胞表面，已经用鞘磷脂酶抑制剂预处理。相反，增强的GAβ依赖性淀粉样蛋白生成的内吞功能障碍，这是AD的细胞病理特征之一，被抑制预处理与SM合酶抑制剂。这表明SM是GAβ生成的关键分子之一，并进一步暗示Aβ与膜脂质的相互作用在脑中淀粉样蛋白纤维化中是关键的。
The assembly of amyloid β-protein into fibrils is an initial event of Alzheimer's disease (AD). Previous studies suggest that ganglioside-bound amyloid β-protein (Aβ), GAβ, is an endogenous seed for amyloid in Alzheimer's disease (AD) brain and that GAβ is generated in the membrane microdomains, comprising cholesterol, sphingomyelin (SM) and GM1 ganglioside. In this study, we showed that the GAβ-dependent amyloidogenesis was accelerated on the surface of PC12 cells that had been pretreated with a sphingomyelinase inhibitor. Conversely, the enhanced GAβ-dependent amyloidogenesis under the endocytic dysfunction, which is one of the cell-pathological features of AD, was suppressed by pretreatment with a SM synthase inhibitor. These suggest that SM is one of the key molecules for GAβ generation and further imply that the interaction of Aβ with membrane lipids is critical in amyloid fibrillization in the brain.