Comparison between the Aggregation of Human and Rodent Amyloid beta-Proteins in GM1 Ganglioside Clusters.
Comparison between the Aggregation of Human and Rodent Amyloid beta-Proteins in GM1 Ganglioside Clusters.
复制标题
人类和啮齿动物淀粉样蛋白 GM1 神经节苷脂簇中聚集的比较。
DOI：
10.1021/bi501239q
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发表时间：
2014
期刊：
影响因子：
2.9
通讯作者：
M. Hoshino & K. Matsuzaki
中科院分区：
文献类型：
--
作者：
H. Ueno;T. Yamaguchi;S. Fukunaga;Y. Okada;Y. Yano;M. Hoshino & K. Matsuzaki
淀粉样β蛋白（amyloid-β protein，Aβ）异常沉积淀粉样蛋白是阿尔茨海默病（Alzheimer's disease，AD）的病理标志。老年啮齿动物很少出现这种疾病的特征性病变，这与人类的情况不同。啮齿动物Aβ（rAβ）与人类Aβ（hAβ）的不同之处仅在于分别在5、10和13位的Arg至Gly、Tyr至Phe和His至Arg的三个取代。了解啮齿类动物Aβ不形成淀粉样蛋白的原因对于揭示病理条件下导致Aβ异常聚集的因素具有重要意义。我们认为，Aβ与神经节苷脂簇的膜结合在Aβ的异常聚集中起重要作用。在这项研究中，我们比较了hAβ和rAβ在神经元细胞、筏状模型膜和缓冲液中的聚集情况。我们发现rAβ在缓冲溶液中形成类似于hAβ的淀粉样纤维。相比之下，在细胞膜和筏状膜上，hAβ形成毒性成熟的淀粉样原纤维，而rAβ产生毒性较小的原纤维，这些原纤维不被淀粉样蛋白特异性染料刚果红染色。因此，我们的神经节苷脂簇介导的淀粉样蛋白生成假说解释了啮齿动物对大脑Aβ淀粉样蛋白沉积的免疫力，强化了神经节苷脂簇作为AD病理学中异常Aβ沉积平台的重要性。
The abnormal deposition of amyloids by amyloid-β protein (Aβ) is a pathological hallmark of Alzheimer’s disease (AD). Aged rodents rarely develop the characteristic lesions of the disease, which is different from the case in humans. Rodent Aβ (rAβ) differs from human Aβ (hAβ) only in the three substitutions of Arg to Gly, Tyr to Phe, and His to Arg at positions 5, 10, and 13, respectively. Understanding the reason why rodent Aβ does not form amyloids is important to revealing factors that cause the abnormal aggregation of Aβ under pathologic conditions. We have proposed that the binding of Aβ to membranes with ganglioside clusters plays an important role in the abnormal aggregation of Aβ. In this study, we compared hAβ and rAβ in terms of aggregation on neuronal cells, on raftlike model membranes, and in buffer. We found that rAβ formed amyloid fibrils similar to those of hAβ in buffer solution. In contrast, on cell membranes and raftlike membranes, hAβ formed toxic, mature amyloid fibrils, whereas rAβ produced less toxic protofibrils that were not stained by the amyloid-specific dye Congo red. Thus, our ganglioside cluster-mediated amyloidogenesis hypothesis explains the immunity of rodents from cerebral Aβ amyloid deposition, strengthening the importance of ganglioside clusters as a platform of abnormal Aβ deposition in the pathology of AD.