Comparison between the Aggregation of Human and Rodent Amyloid 尾-Proteins in GM1 Ganglioside Clusters

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• 作者：Hiroshi Ueno ; Takahiro Yamaguchi ; Saori Fukunaga ; Yuki Okada ; Yoshiaki Yano ; Masaru Hoshino ; Katsumi Matsuzaki
• 刊名：Biochemistry
• 出版年：2014
• 出版时间：December 9, 2014
• 年：2014
• 卷：53
• 期：48
• 页码：7523-7530
• 全文大小：403K
• ISSN：1520-4995

文摘

The abnormal deposition of amyloids by amyloid-尾 protein (A尾) is a pathological hallmark of Alzheimer鈥檚 disease (AD). Aged rodents rarely develop the characteristic lesions of the disease, which is different from the case in humans. Rodent A尾 (rA尾) differs from human A尾 (hA尾) 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 A尾 does not form amyloids is important to revealing factors that cause the abnormal aggregation of A尾 under pathologic conditions. We have proposed that the binding of A尾 to membranes with ganglioside clusters plays an important role in the abnormal aggregation of A尾. In this study, we compared hA尾 and rA尾 in terms of aggregation on neuronal cells, on raftlike model membranes, and in buffer. We found that rA尾 formed amyloid fibrils similar to those of hA尾 in buffer solution. In contrast, on cell membranes and raftlike membranes, hA尾 formed toxic, mature amyloid fibrils, whereas rA尾 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 A尾 amyloid deposition, strengthening the importance of ganglioside clusters as a platform of abnormal A尾 deposition in the pathology of AD.