Correlation of β-amyloid aggregate size and hydrophobicity with decreased bilayer fluidity of model membranes
Correlation of β-amyloid aggregate size and hydrophobicity with decreased bilayer fluidity of model membranes
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DOI：
10.1021/bi0001980
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发表时间：
2000-08-22
期刊：
影响因子：
2.9
通讯作者：
Murphy, RM
中科院分区：
文献类型：
--
作者：
Kremer, JJ;Pallitto, MM;Murphy, RM
β-淀粉样肽（A β）是老年斑的主要成分，老年斑是阿尔茨海默氏病的一个定义性特征。聚集的A β对神经元有毒，但毒性机制尚未得到证实。一种观点认为A β毒性是由相对非特异性的A β-膜相互作用引起的。我们假设A β干扰膜结构作为A β聚集状态的函数。为了探索这一假设，使用动态和静态光散射和1，1-双（4-苯胺基）萘-5，5-二磺酸（bis-ANS）荧光来表征A β聚集体大小和疏水性。通过监测膜包埋的荧光染料16-二苯基-1，3，5-己三烯（DPH）的各向异性来评估A β聚集状态对单层脂质体的膜流动性的影响。在pH 7下未聚集的A β不结合bis-ANS，并且对膜流动性几乎没有影响。更重要的是，在pH 6或7聚集的A β以时间和剂量依赖性方式降低膜流动性。聚集率和表面疏水性是相当大的A β聚集在pH 6比在中性pH值，并与膜流动性的降低程度密切相关。延长（7天）A β聚集导致在pH 7下，但在pH 6下，bis-ANS荧光和DPH各向异性均恢复到接近基线水平。加入神经节苷脂的脂质体显着增加的DPH各向异性响应。因此，A β单体自缔合成聚集体暴露疏水位点并诱导膜流动性降低。β聚集体诱导的膜物理性质的变化可能对细胞功能产生有害后果。
beta-amyloid peptide (A beta) is the primary constituent of senile plaques, a defining feature of Alzheimer' s disease. Aggregated A beta is toxic to neurons, but the mechanism of toxicity remains unproven. One proposal is that A beta toxicity results from relatively nonspecific A beta-membrane interactions. We hypothesized that A beta perturbs membrane structure as a function of the aggregation state of A beta. Toward exploring this hypothesis, A beta aggregate size and hydrophobicity were characterized using dynamic and static light scattering and 1,1 -bis(4-anilino)naphthalene-5,5-disulfonic acid (bis-ANS) fluorescence. The effect of A beta aggregation state on the membrane fluidity of unilamellar liposomes was assessed by monitoring the anisotropy of the membrane-embedded fluorescent dye, 1 6-diphenyl-1,3,5-hexatriene (DPH), Unaggregated A beta at pH 7 did not bind bis-ANS and had little to no effect on membrane fluidity. More significantly, A beta aggregated at pH 6 or 7 decreased membrane fluidity in a time- and dose-dependent manner. Aggregation rate and surface hydrophobicity were considerably greater for A beta aggregated at pH 6 than at neutral pH and were strongly correlated with the extent of decrease in membrane fluidity. Prolonged (7 days) A beta aggregation resulted in a return to near-baseline levels in both bis-ANS fluorescence and DPH anisotropy at pH 7 but not at pH 6. The addition of gangliosides to the liposomes significantly increased the DPH anisotropy response. Hence, self-association of A beta monomers into aggregates exposes hydrophobic sites and induces a decrease in membrane fluidity. A beta aggregate-induced changes in membrane physical properties may have deleterious consequences on cellular functioning.