Xin Yang, Diling Chen, Jian Yang, Ting Liu, Guoyan Hu, Hualun Liang, Xiaocui Tang, Guoxiao Lai, Ou Shuai, Chaoqun Zheng, Jun Zhao, Yizhen Xie
Department of Pharmacy, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
The Fifth Clinical School of Guangzhou Medical University, Guangzhou, China.
Front Neurol. 2018 Jun 15;9:412. doi: 10.3389/fneur.2018.00412. eCollection 2018.
Alzheimer's disease (AD), a progressive neurodegenerative disorder, lacks preclinical diagnostic biomarkers and therapeutic drugs. Thus, earlier intervention in AD is a top priority. Studies have shown that the gut microbiota influences central nervous system disorders and that prebiotics can improve the cognition of hosts with AD, but these effects are not well understood. Preliminary research has shown that oligosaccharides from (OMO) are a useful prebiotic and cause substantial memory improvements in animal models of AD; however, the mechanism is still unclear. Therefore, this study was conducted to investigate whether OMO are clinically effective in alleviating AD by improving gut microbiota. OMO were administered to APP/PS1 transgenic mice, and potential clinical biomarkers of AD were identified with metabolomics and bioinformatics. Behavioral experiments demonstrated that OMO significantly ameliorated the memory of the AD animal model. Histological changes indicated that OMO ameliorated brain tissue swelling and neuronal apoptosis and downregulated the expression of the intracellular AD marker Aβ. 16S rRNA sequencing analyses indicated that OMO maintained the diversity and stability of the microbial community. The data also indicated that OMO are an efficacious prebiotic in an animal model of AD, regulating the composition and metabolism of the gut microbiota. A serum metabolomics assay was performed using UHPLC-LTQ Orbitrap mass spectrometry to delineate the metabolic changes and potential early biomarkers in APP/PS1 transgenic mice. Multivariate statistical analysis showed that 14 metabolites were significantly upregulated, and 8 metabolites were downregulated in the model animals compared to the normal controls. Thus, key metabolites represent early indicators of the development of AD. Overall, we report a drug and signaling pathway with therapeutic potential, including proteins associated with cognitive deficits in normal mice or gene mutations that cause AD.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，缺乏临床前诊断生物标志物和治疗药物。因此，对AD进行早期干预是当务之急。研究表明，肠道微生物群会影响中枢神经系统疾病，益生元可以改善AD宿主的认知，但这些作用尚未得到充分了解。初步研究表明，海洋寡糖（OMO）是一种有用的益生元，可在AD动物模型中显著改善记忆；然而，其机制仍不清楚。因此，本研究旨在调查OMO是否通过改善肠道微生物群在临床上有效缓解AD。将OMO给予APP/PS1转基因小鼠，并通过代谢组学和生物信息学鉴定AD的潜在临床生物标志物。行为实验表明，OMO显著改善了AD动物模型的记忆。组织学变化表明，OMO减轻了脑组织肿胀和神经元凋亡，并下调了细胞内AD标志物Aβ的表达。16S rRNA测序分析表明，OMO维持了微生物群落的多样性和稳定性。数据还表明，OMO在AD动物模型中是一种有效的益生元，可调节肠道微生物群的组成和代谢。使用超高效液相色谱-线性离子阱静电场轨道阱质谱仪进行血清代谢组学分析，以描绘APP/PS1转基因小鼠的代谢变化和潜在的早期生物标志物。多变量统计分析表明，与正常对照组相比，模型动物中有14种代谢物显著上调，8种代谢物下调。因此，关键代谢物代表了AD发展的早期指标。总体而言，我们报告了一种具有治疗潜力的药物和信号通路，包括与正常小鼠认知缺陷相关的蛋白质或导致AD的基因突变。
