Inhibitors of amyloid beta-protein aggregation mediated by GM1-containing raft-like membranes.
Inhibitors of amyloid beta-protein aggregation mediated by GM1-containing raft-like membranes.
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DOI：
10.1016/j.bbamem.2006.09.014
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发表时间：
2007
期刊：
影响因子：
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通讯作者：
K. Matsuzaki;T. Noguch;M. Wakabayashi;Keisuke Ikeda;Takuma Okada;Y. Ohashi;M. Hoshino;H. Naiki
中科院分区：
文献类型：
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作者：
K. Matsuzaki;T. Noguch;M. Wakabayashi;Keisuke Ikeda;Takuma Okada;Y. Ohashi;M. Hoshino;H. Naiki
淀粉样β蛋白（Aβ）的聚集（纤维形成）被认为是阿尔茨海默病（AD）病因学中的关键步骤。已经广泛研究了通过小化合物抑制Aβ聚集和/或在水溶液中形成的原纤维分解以预防和治疗AD。然而，最近的研究表明，Aβ聚集也发生在由单唾液酸神经节苷脂GM 1簇介导的脂筏中。本研究检查了在含有GM 1的筏状脂质体存在下代表性化合物对Aβ聚集和原纤维不稳定的影响。其中去甲二氢愈创木酸（NDGA）、利福平（RIF）、鞣酸（TA）和槲皮素（QUE）具有较强的抗纤维化活性。NDGA和RIF通过竞争性结合膜和/或与溶液中的Aβ直接相互作用抑制Aβ与GM 1脂质体的结合，从而至少部分阻止原纤维形成。在存在GM 1脂质体的情况下，Aβ与NDGA、RIF和QUE共孵育产生细长颗粒，而存在TA则产生原纤维结构。TA和RIF也使原纤维不稳定。最有效的NDGA通过抑制Aβ蓄积来防止Aβ诱导的PC 12细胞毒性。此外，各种化合物对水相和GM 1介导的Aβ聚集的抑制作用的比较表明，这两种聚集过程并不相同。
The aggregation (fibril formation) of amyloid β-protein (Aβ) is considered to be a crucial step in the etiology of Alzheimer's disease (AD). The inhibition of Aβ aggregation and/or decomposition of fibrils formed in aqueous solution by small compounds have been studied extensively for the prevention and treatment of AD. However, recent studies suggest that Aβ aggregation also occurs in lipid rafts mediated by a cluster of monosialoganglioside GM1. This study examined the effects of representative compounds on Aβ aggregation and fibril destabilization in the presence of GM1-containing raft-like liposomes. Among the compounds tested, nordihydroguaiaretic acid (NDGA), rifampicin (RIF), tannic acid (TA), and quercetin (QUE) showed strong fibrillization inhibitory activity. NDGA and RIF inhibited the binding of Aβ to GM1 liposomes by competitively binding to the membranes and/or direct interaction with Aβ in solution, thus at least partly preventing fibrils from forming. Coincubation of Aβ with NDGA, RIF, and QUE in the presence of GM1 liposomes resulted in elongate particles, whereas the presence of TA yielded protofibrillar structures. TA and RIF also destabilized fibrils. The most potent NDGA prevented Aβ-induced toxicity in PC12 cells by inhibiting Aβ accumulation. Furthermore, a comparison of the inhibitory effects of various compounds between aqueous-phase and GM1-mediated aggregation of Aβ suggested that the two aggregation processes are not identical.