Ferulic Acid Inhibits the Transition of Amyloid-β42 Monomers to Oligomers but Accelerates the Transition from Oligomers to Fibrils
Ferulic Acid Inhibits the Transition of Amyloid-β42 Monomers to Oligomers but Accelerates the Transition from Oligomers to Fibrils
复制标题
DOI：
10.3233/jad-130164
复制
发表时间：
2013-01-01
影响因子：
4
通讯作者：
Zhang, Yingjiu
中科院分区：
文献类型：
--
作者：
Cui, Lili;Zhang, Yuan;Zhang, Yingjiu
阿尔茨海默病（AD）是一种神经退行性疾病，发生在老年人群中，与认知功能受损有关。 β 淀粉样蛋白 (Aβ) 寡聚体引发病理级联反应，是 AD 的神经病理性标志。因此，抑制Aβ聚集的方法是治疗AD的一种有吸引力的治疗策略。阿魏酸 (FA) 是一种酚类化合物，可在体外和体内抑制 A beta(42) 原纤维诱导的细胞毒性。然而，很少有研究证明 FA 与 A beta(42) 寡聚物相互作用。在这里，我们研究了 FA 是否抑制 A beta(42) 寡聚物诱导的细胞毒性以及 FA 对 A beta 聚集的影响。我们的结果表明，FA 降低了 A beta(42) 诱导的 SH-SY5Y 细胞神经毒性。此外，使用 CD 光谱，我们发现 FA 抑制了 A beta(42) 单体到低聚物转变所需的 β-折叠的形成，但加速了 A beta(42) 低聚物到原纤维的转变。这些现象通过透射电子显微镜和硫代黄素T荧光测定得到证实。 FA与Aβ(42)单体之间的对接分析表明，FA可能通过阻断与形成的β-折叠的氢键来抑制Aβ(42)寡聚体的聚集。综上所述，我们发现了一种新现象，即 FA 抑制 A β(42) 寡聚物的形成，同时加速 A β(42) 寡聚物向原纤维的转变，并且我们已经证明 FA 通过阻止 A β(42) 形成寡聚物来防止 A β(42) 诱导的体外毒性。
Alzheimer's disease (AD) is neurodegenerative disease that occurs among the aging population and is associated with impaired cognitive function. Amyloid-beta (A beta) oligomers initiate the pathological cascade and represent a neuropathic hallmark of AD. Therefore, an approach that inhibits A beta aggregation is an attractive therapeutic strategy for the treatment of AD. Ferulic acid (FA) is a phenolic compound that can inhibit A beta(42) fibril-induced cytotoxicity both in vitro and in vivo. However, few studies have demonstrated that FA interacts with A beta(42) oligomers. Here, we investigated whether FA inhibits A beta(42) oligomer-induced cytotoxicity and the effect of FA on A beta aggregation. Our results showed that FA reduced A beta(42)-induced neurotoxicity in SH-SY5Y cells. Moreover, using CD spectroscopy, we found that FA inhibited the formation of the beta-sheets that are required for the A beta(42) monomer-to-oligomer transition but accelerated the A beta(42) oligomer-to-fibril transition. These phenomena were confirmed by transmission electron microscopy and thioflavin T fluorescence assay. The docking analysis between FA and A beta(42) monomer showed that FA may inhibit the aggregation of A beta(42) oligomers by blocking the hydrogen bond with the forming beta-sheets. Taken together, we have identified a novel phenomenon in which FA inhibits the formation of A beta(42) oligomers while accelerating the transition of A beta(42) oligomers to fibrils, and we have shown that FA protects against A beta(42)-induced toxicity in vitro by preventing A beta(42) from forming oligomers.