Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
Biochemistry. 2011 Jul 26;50(29):6433-40. doi: 10.1021/bi200771m. Epub 2011 Jun 29.
It is widely accepted that the conversion of the soluble, nontoxic amyloid β-protein (Aβ) monomer to aggregated toxic Aβ rich in β-sheet structures is central to the development of Alzheimer's disease. However, the mechanism of the abnormal aggregation of Aβ in vivo is not well understood. We have proposed that ganglioside clusters in lipid rafts mediate the formation of amyloid fibrils by Aβ, the toxicity and physicochemical properties of which are different from those of amyloids formed in solution. In this paper, the mechanism by which Aβ-(1-40) fibrillizes in raftlike lipid bilayers composed of monosialoganglioside GM1, cholesterol, and sphingomyelin was investigated in detail on the basis of singular-value decomposition of circular dichroism data and analysis of fibrillization kinetics. At lower protein densities in the membrane (Aβ:GM1 ratio of less than ∼0.013), only the helical species exists. At intermediate protein densities (Aβ:GM1 ratio between ∼0.013 and ∼0.044), the helical species and aggregated β-sheets (∼15-mer) coexist. However, the β-structure is stable and does not form larger aggregates. At Aβ:GM1 ratios above ∼0.044, the β-structure is converted to a second, seed-prone β-structure. The seed recruits monomers from the aqueous phase to form amyloid fibrils. These results will shed light on a molecular mechanism for the pathogenesis of the disease.
普遍认为，可溶性无毒的淀粉样β蛋白（Aβ）单体转化为富含β-折叠结构的聚集性有毒 Aβ是阿尔茨海默病发展的核心。然而，Aβ 在体内异常聚集的机制尚不清楚。我们提出神经节苷脂簇在脂筏中介导 Aβ形成淀粉样纤维，其毒性和物理化学性质与溶液中形成的淀粉样纤维不同。在本文中，我们根据圆二色性数据的奇异值分解和纤维形成动力学分析，详细研究了由单唾液酸神经节苷脂 GM1、胆固醇和鞘磷脂组成的类脂筏双层中 Aβ-（1-40）的纤维形成机制。在膜中较低的蛋白密度（Aβ：GM1 比值小于约 0.013）下，仅存在螺旋态。在中间蛋白密度（Aβ：GM1 比值在约 0.013 和约 0.044 之间）下，螺旋态和聚集的β-片层（约 15 聚体）共存。然而，β-结构是稳定的，不会形成更大的聚集体。当 Aβ：GM1 比值高于约 0.044 时，β-结构转化为第二种、具有成核倾向的β-结构。该成核结构从水相中招募单体形成淀粉样纤维。这些结果将为该疾病的发病机制提供分子机制方面的启示。
