Wu Mengnan, Chen Yan-Fen, Yao Wei, Zhou Siyan, Xie Zuolei, Tao Ye, Zhong Yi, Ma Weiwei
School of Life Sciences, Tsinghua University, Beijing, 100084, China.
Beijing Joekai Biotechnology LLC, Beijing, 100094, China.
Sci Rep. 2025 Apr 13;15(1):12720. doi: 10.1038/s41598-025-91785-4.
Neuroinflammation precedes the clinical symptoms onset of Alzheimer's disease (AD) by decades. However, the anti-inflammatory drugs were not always effective at all stages of the disease. Here, using the fly and mouse AD models, we evaluated the effects of anti-inflammatory drugs on inflammatory-related factors and the proinflammatory cytokines at different ages of AD animals. We also performed behavioral tests to evaluate the cognitive aspects of AD. Combined with the bioinformatics analysis, we would like to exhibit a better understanding of AD. Based on the previous studies and reanalysis of published database, we found aged AD animals might better represent the inflammatory status of symptomatic AD. Our results showed that mRNA levels of antimicrobial peptides (AMPs) were highly expressed in 10-day-old AD flies, while no significant difference was observed in 40-day-old AD. In aged APP/PS1 mice (22.5 months), inflammatory-related factors NF-κB, IBA1, and the mRNA levels of proinflammatory cytokines Il-1β and Il-6 were not differentially expressed. In contrast, a significant increase was observed in 7.5-month-old APP/PS1 mice. Moreover, the anti-inflammatory drug Montelukast (MON) did not ameliorate the inflammatory and cognitive defects in 22.5-month-old aged mice but showed a rescue effect in 7.5-month-old young APP/PS1 mice. Altogether, our study demonstrates the different inflammatory status might lead to variations of anti-inflammatory drug efficacy, which helps to clarify the importance of considering the pathological stage of the disease when administering treatment.
神经炎症在阿尔茨海默病（AD）临床症状出现前数十年就已存在。然而，抗炎药物在该疾病的所有阶段并非都有效。在此，我们使用果蝇和小鼠AD模型，评估了抗炎药物对AD动物不同年龄阶段炎症相关因子和促炎细胞因子的影响。我们还进行了行为测试以评估AD的认知方面。结合生物信息学分析，我们希望能更好地理解AD。基于先前的研究以及对已发表数据库的重新分析，我们发现老年AD动物可能更能代表有症状AD的炎症状态。我们的结果表明，抗菌肽（AMPs）的mRNA水平在10日龄的AD果蝇中高表达，而在40日龄的AD果蝇中未观察到显著差异。在老年APP/PS1小鼠（22.5个月）中，炎症相关因子NF-κB、IBA1以及促炎细胞因子Il-1β和Il-6的mRNA水平没有差异表达。相比之下，在7.5个月大的APP/PS1小鼠中观察到显著增加。此外，抗炎药物孟鲁司特（MON）并未改善22.5个月大的老年小鼠的炎症和认知缺陷，但在7.5个月大的年轻APP/PS1小鼠中显示出挽救作用。总之，我们的研究表明不同的炎症状态可能导致抗炎药物疗效的差异，这有助于阐明在给药治疗时考虑疾病病理阶段的重要性。
