<b>Investigating Metabolic Dysregulation in Serum of Triple Transgenic Alzheimer's Disease Male Mice: Implications for Pathogenesis and Potential Biomarkers</b>

<strong>Introduction</strong> Alzheimer's disease (AD) is considered to be a multifactorial neurodegenerative disease that lacks effective drugs. <strong>Objective</strong> Pathological changes in the brain can be reflected in blood metabolites that are expected to explain the disease mechanisms or be candidate biomarkers. <strong>Methods</strong> Targeted metabolomics was used to quantify 256 metabolites in serum of triple transgenic AD (3×Tg-AD) male mice. <strong>Resutls</strong> Compared with control, 49 metabolites involved in bioamines and nucleoside analogues were identified as differential metabolites. They mainly were associated with purine, pyrimidine, tryptophan, cysteine and methionine and glycerophospholipid metabolism, of which the significant ones included decreased serum levels of adenosine, serotonin, N-acetyl-5-hydroxytryptamine, S-adenosine-L-homocysteine, and CDP-choline, and increased serum levels of S-adenosine-L-methionine, acetylcholine, and trimethylamine-N-oxide in AD mice. <strong>Conclusion</strong> The results revealed the changes of neuromodulators in serum, suggesting that dysregulated metabolites in periphery in AD mice may be related to the disturbances in neuroinhibition, the serotonergic system, sleep function, the cholinergic system, and the gut microbiota. The study proposed the possibility of developing peripheral biomarkers in early AD.**引言**：阿尔茨海默病（Alzheimer's disease, AD）是一种多因素神经退行性疾病，目前尚无有效治疗药物。 **研究目的**：脑部的病理变化可反映于血液代谢物中，此类代谢物有望用于阐释疾病发病机制或作为候选生物标志物。 **研究方法**：本研究采用靶向代谢组学（targeted metabolomics）技术，对三转基因阿尔茨海默病（3×Tg-AD）雄性小鼠的血清样本中256种代谢物进行定量分析。 **研究结果**：与对照组相比，共鉴定出49种涉及生物胺（bioamines）与核苷类似物（nucleoside analogues）的差异代谢物。这些代谢物主要与嘌呤、嘧啶、色氨酸、半胱氨酸与甲硫氨酸及甘油磷脂代谢通路相关；其中显著变化的代谢物包括：AD模型小鼠血清中腺苷、血清素、N-乙酰-5-羟色胺、S-腺苷-L-同型半胱氨酸及CDP-胆碱水平降低，而S-腺苷-L-甲硫氨酸、乙酰胆碱与氧化三甲胺（trimethylamine-N-oxide）水平升高。 **研究结论**：本研究结果揭示了血清中神经调节因子的变化情况，提示AD模型小鼠外周代谢紊乱可能与神经抑制功能、血清素能系统、睡眠功能、胆碱能系统及肠道菌群失衡相关。本研究提出了开发早期阿尔茨海默病外周生物标志物的可行性。