Liu Weiying, Sun Fengxian, Wan Moxin, Jiang Fang, Bo Xiangyu, Lin Laixiang, Tang Hua, Xu Shumei
Department of Pathogen Biology, Tianjin Life Science Research Center, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Front Pharmacol. 2018 Jan 8;8:969. doi: 10.3389/fphar.2017.00969. eCollection 2017.
Alzheimer's disease (AD), is a progressive neurodegenerative disease that is characterized by cognitive loss. Most researchers believe that aggregation and accumulation of β-amyloid peptides (Aβ) in brain cells are the central pathological hallmark of this disease. Based on the amyloid hypothesis, a 10 amino acids β-sheet breaker peptide HPYD (His-Lys-Gln-Leu-Pro-Phe-Tyr-Glu-Glu-Asp) was designed according to the structure and sequence of the previous designed peptide H102. Accelerated stability test, thioflavine T (ThT) fluorescence spectral analysis and transmission electron microscopy (TEM) imaging were performed to detect the stability and inhibitory effects on the aggregation of Aβ by H102 and HPYD. FITC-labeled HPYD was first tested to determine whether it could be transferred along the olfactory pathway to the brain after nasal administration to mice. Subsequently, the Morris Water Maze (MWM) test for behavioral analysis was used to investigate the learning and memory ability of APP/PS1 transgenic mice by HPYD. Immunohistochemistry and western blot analysis was performed to determine the role of HPYD on Aβ and APP protein levels. In addition, microarray analysis was used to evaluate the effect of HPYD on gene expression in AD mouse models. Our results demonstrated that HPYD had enhanced stability and inhibitory effects on Aβ aggregation compared to H102. HPYD could be delivered into the brain through nasal administration and improved the learning and memory ability in APP/PS1 transgenic mouse models by reducing Aβ and APP protein levels. In addition, microarray analyses suggested that several genes related to the inflammatory pathway, AD and gluco-lipid metabolism were dysregulated and could be restored to almost normal levels after HPYD administration to mice. Our results demonstrated that HPYD could be a potential therapeutic drug candidate for the treatment of AD.
阿尔茨海默病（AD）是一种以认知功能丧失为特征的进行性神经退行性疾病。大多数研究人员认为，β-淀粉样肽（Aβ）在脑细胞中的聚集和积累是这种疾病的核心病理标志。基于淀粉样蛋白假说，根据先前设计的肽H102的结构和序列设计了一种10个氨基酸的β-折叠破坏肽HPYD（His-Lys-Gln-Leu-Pro-Phe-Tyr-Glu-Glu-Asp）。进行加速稳定性试验、硫黄素T（ThT）荧光光谱分析和透射电子显微镜（TEM）成像，以检测H102和HPYD对Aβ聚集的稳定性和抑制作用。首先测试了异硫氰酸荧光素（FITC）标记的HPYD，以确定其经鼻腔给药给小鼠后是否能沿嗅觉通路转移到大脑。随后，使用莫里斯水迷宫（MWM）行为分析试验来研究HPYD对APP/PS1转基因小鼠学习和记忆能力的影响。进行免疫组织化学和蛋白质印迹分析，以确定HPYD对Aβ和APP蛋白水平的作用。此外，利用基因芯片分析评估HPYD对AD小鼠模型基因表达的影响。我们的结果表明，与H102相比，HPYD对Aβ聚集具有更高的稳定性和抑制作用。HPYD可以通过鼻腔给药进入大脑，并通过降低Aβ和APP蛋白水平来改善APP/PS1转基因小鼠模型的学习和记忆能力。此外，基因芯片分析表明，一些与炎症途径、AD和糖脂代谢相关的基因表达失调，在给小鼠施用HPYD后可恢复到几乎正常水平。我们的结果表明，HPYD可能是一种治疗AD的潜在候选治疗药物。
