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首页> 外文期刊>Journal of Molecular Biology >Formation of amyloids by Abeta-(1-42) on NGF-differentiated PC12 cells: roles of gangliosides and cholesterol.
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Formation of amyloids by Abeta-(1-42) on NGF-differentiated PC12 cells: roles of gangliosides and cholesterol.

机译：由Abeta-（1-42）在NGF分化的PC12细胞上形成淀粉样蛋白：神经节苷脂和胆固醇的作用。

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The conversion of soluble, non-toxic amyloid beta-protein (Abeta) to aggregated, toxic Abeta could be the key step in the development of Alzheimer's disease. Liposomal studies have proposed that Abeta-(1-40) preferentially recognizes a cholesterol-dependent cluster of gangliosides and a conformationally altered form of Abeta promotes the aggregation of the protein. Cell experiments using fluorescein-labeled Abeta-(1-40) supported this model. Here, the interaction of native Abeta-(1-42) with unfixed rat pheochromocytoma PC12 cells was visualized using the amyloid-specific dye Congo red. Abeta-(1-42) preferentially bound to ganglioside and cholesterol-rich domains of cell membranes and formed amyloids in a time-dependent manner. These observations corroborate the model involving ganglioside-mediated accumulation of Abeta. The NGF-induced differentiation of PC12 cells into neuron-like cells caused a marked increase in both gangliosides and cholesterol, and thereby greatly potentiated the accumulation and cytotoxicity of Abeta-(1-42). NGF-differentiated cells exposed to Abeta-(1-42) had degenerated neurites, in which ganglioside and cholesterol-rich domains were localized, preceding cell death. A reduction in the amount of cholesterol by the cholesterol synthesis inhibitor compactin almost nullified the formation of amyloids by Abeta-(1-42). Our system using NGF-differentiated PC12 cells and Congo red is useful for screening inhibitors of the formation of amyloids by and cytotoxicity of Abeta.
机译：可溶性，无毒的淀粉样β蛋白（Abeta）向聚集的有毒Abeta的转化可能是阿尔茨海默氏病发展的关键步骤。脂质体研究提出，Abeta-（1-40）优先识别神经节苷脂的胆固醇依赖性簇，Abeta的构象改变形式促进蛋白质的聚集。使用荧光素标记的Abeta-（1-40）的细胞实验支持该模型。在这里，使用淀粉样蛋白特异性染料刚果红可视化天然Abeta-（1-42）与未固定的大鼠嗜铬细胞瘤PC12细胞的相互作用。 Abeta-（1-42）优先绑定到神经节苷脂和富含胆固醇的细胞膜结构域，并以时间依赖性方式形成淀粉样蛋白。这些观察结果证实了涉及神经节苷脂介导的Abeta积累的模型。 NGF诱导PC12细胞分化为神经元样细胞导致神经节苷脂和胆固醇均明显增加，从而大大增强了Abeta-（1-42）的积累和细胞毒性。暴露于Abeta-（1-42）的NGF分化细胞具有变性的神经突，其中神经节苷脂和富含胆固醇的域位于细胞死亡之前。胆固醇合成抑制剂紧密蛋白降低胆固醇的量几乎使Abeta-（1-42）形成的淀粉样蛋白无效。我们使用NGF分化的PC12细胞和刚果红的系统可用于筛选Abeta形成淀粉样蛋白抑制剂和Abeta的细胞毒性。

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