Yan Yu-Hui, Huang Zi-Han, Xiong Qing-Ping, Song Yue-Wen, Li Si-Yang, Yang Bao-Wei, Sun Lan, Zhang Meng-Yuan, Ji Yu
School of Pharmacy, Jiangsu Food & Pharmaceutical Science College, Huai'an, Jiangsu, China.
School of Food Science and Engineering, Jiangsu Ocean University, Lianyungang, Jiangsu, China.
Front Pharmacol. 2022 Oct 26;13:1056614. doi: 10.3389/fphar.2022.1056614. eCollection 2022.
Adult neurogenesis plays an important role in repairing damaged neurons and improving cognitive impairment in Alzheimer's disease (AD). (L.) L'Hér. ex Vent. fruits (BL), a traditional Chinese medicine for tonifying the kidney, has been reported to improve cognitive function in AD mice, but the underlying mechanisms have not been clearly illuminated. This study aimed to provide an overview of the differential compounds in the brain of APP/PS1 mice after BL water extract (BLWE) treatment through metabolomics technology and to elucidate whether the therapeutic effect and mechanism are through the enhancement of neurogenesis. APP/PS1 transgenic mice were treated with different doses of BLWE. After 6 weeks of intragastric injection, the therapeutic effects of BLWE on APP/PS1 transgenic mice were determined by the Morris water maze test, immunohistochemistry, hematoxylin & eosin and Nissl staining, enzyme-linked immunosorbent assay and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Subsequently, metabolomics technology was used to analyze the regulatory effect of BLWE on differential compounds in the brain of APP/PS1 mice, and on this basis, its molecular mechanism of BLWE was screened. Finally, the protein expression of the Wnt/β-catenin signaling pathway was detected by Western blotting. After BLWE treatment, the learning and memory function of APP/PS1 mice were significantly improved, which was related to the increase in the number of Nestin/BrdU and NeuN/BrdU cells, and the decrease in the number of apoptotic cells in the hippocampus. BLWE treatment could also up-regulate the expression of synapse-associated proteins. Moreover, BLWE could modulate endogenous metabolic compounds in the brains of AD mice, including N-acetyl-aspartate, glutamine, etc. Furthermore, BLWE inhibited the phosphorylation of Tyr216-GSK-3β and β-catenin protein while increased CyclinD protein expression. We demonstrated that BLWE can enhance neural stem cells proliferation and improve neurogenesis, thereby efficiently repairing damaged neurons in the hippocampus and ameliorating cognitive impairment in APP/PS1 transgenic mice. The mechanism is at least partly through activating the Wnt/β-catenin signaling pathway.
成体神经发生在修复受损神经元和改善阿尔茨海默病（AD）的认知障碍中发挥着重要作用。补肾中药巴戟天（Morinda officinalis How）果实（BL）已被报道可改善AD小鼠的认知功能，但其潜在机制尚未明确阐明。本研究旨在通过代谢组学技术概述BL水提取物（BLWE）处理后APP/PS1小鼠大脑中的差异化合物，并阐明其治疗效果和机制是否通过增强神经发生来实现。将不同剂量的BLWE给予APP/PS1转基因小鼠。胃内注射6周后，通过莫里斯水迷宫试验、免疫组织化学、苏木精-伊红和尼氏染色、酶联免疫吸附测定以及末端脱氧核苷酸转移酶dUTP缺口末端标记染色来确定BLWE对APP/PS1转基因小鼠的治疗效果。随后，利用代谢组学技术分析BLWE对APP/PS1小鼠大脑中差异化合物的调节作用，并在此基础上筛选其分子机制。最后，通过蛋白质免疫印迹法检测Wnt/β-连环蛋白信号通路的蛋白表达。BLWE处理后，APP/PS1小鼠的学习和记忆功能显著改善，这与海马中巢蛋白/溴脱氧尿苷（Nestin/BrdU）和神经元核抗原/溴脱氧尿苷（NeuN/BrdU）细胞数量增加以及凋亡细胞数量减少有关。BLWE处理还可上调突触相关蛋白的表达。此外，BLWE可调节AD小鼠大脑中的内源性代谢化合物，包括N-乙酰天门冬氨酸、谷氨酰胺等。此外，BLWE抑制酪氨酸216-糖原合酶激酶-3β（Tyr216-GSK-3β）的磷酸化和β-连环蛋白蛋白，同时增加细胞周期蛋白D（CyclinD）蛋白表达。我们证明，BLWE可增强神经干细胞增殖并改善神经发生，从而有效修复海马中受损的神经元并改善APP/PS1转基因小鼠的认知障碍。其机制至少部分是通过激活Wnt/β-连环蛋白信号通路来实现的。
