Department of Chemistry, National Taiwan Normal University, Taipei 100, Taiwan.
Institute of Medical Science and Technology, National Sun Yat-Sen University, Kaohsiung 800, Taiwan.
J Phys Chem B. 2021 Jun 3;125(21):5559-5571. doi: 10.1021/acs.jpcb.1c02797. Epub 2021 May 21.
Alzheimer's disease (AD) is characterized by the presence of extracellular senile plaques formed by β-amyloid (Aβ) peptides in the patient's brain. Previous studies have shown that the plaques in the AD brains are colocalized with the advanced glycation end products, which is mainly formed from a series of nonenzymatic reactions of proteins with reducing sugars or reactive dicarbonyls. Glycation was also demonstrated to increase the neurotoxicity of the Aβ peptides. To clarify the impact of glycation on Aβ aggregation, we synthesized two glycated Aβ42 peptides by replacing Lys16 and Lys28 with N-carboxymethyllysine respectively to mimic the occurrence of protein glycation. Afterward, we monitored the aggregation kinetics and conformational change for two glycated peptides. We also used fluorescence correlation spectroscopy to probe the early stage of peptide oligomerization and tested their abilities in copper binding and reactive oxygen species production. Our data show that glycation significantly slows down the aggregation process and induces more cytotoxicity especially at position 28. We speculated that the higher toxicity might result from a relatively stable oligomeric form of peptide and not from ROS production. The data shown here emphasized that glycated proteins would be an important therapeutic target in AD treatments.
阿尔茨海默病（AD）的特征是患者大脑中β-淀粉样蛋白（Aβ）肽形成的细胞外老年斑。先前的研究表明，AD 大脑中的斑块与晚期糖基化终产物（AGEs）共定位，AGEs主要由蛋白质与还原糖或反应性二羰基化合物的一系列非酶反应形成。糖化还证明了增加了 Aβ肽的神经毒性。为了阐明糖化对 Aβ聚集的影响，我们通过分别用 N-羧甲基赖氨酸取代 Lys16 和 Lys28 合成了两种糖化 Aβ42 肽，以模拟蛋白质糖化的发生。然后，我们监测了两种糖化肽的聚集动力学和构象变化。我们还使用荧光相关光谱法探测了肽低聚化的早期阶段，并测试了它们在铜结合和活性氧物质产生方面的能力。我们的数据表明，糖化显著减缓了聚集过程，并在位置 28 处诱导出更高的细胞毒性。我们推测，更高的毒性可能是由于肽的相对稳定的寡聚形式，而不是由于 ROS 产生。这里显示的数据强调了糖化蛋白将成为 AD 治疗中的一个重要治疗靶点。
