Zohar Keren, Lezmi Elyad, Reichert Fanny, Eliyahu Tsiona, Rotshenker Shlomo, Weinstock Marta, Linial Michal
Department of Biological Chemistry, Institute of Life Science, Faculty of Science, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Department of Genetics, Institute of Life Science, Faculty of Science, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Int J Mol Sci. 2025 Jun 13;26(12):5677. doi: 10.3390/ijms26125677.
The primary function of microglia is to maintain brain homeostasis. In neurodegenerative diseases like Alzheimer's, microglia contribute to neurotoxicity and inflammation. In this study, we exposed neonatal murine primary microglial cultures to stimuli mimicking pathogens, injury, or toxins. Treatment with benzoyl ATP (bzATP) and lipopolysaccharide (LPS) triggered a coordinated increase in interleukin and chemokine expression. We analyzed statistically significant differentially expressed microRNAs (DEMs) at 3 and 8 h post-activation, identifying 33 and 57 DEMs, respectively. Notably, miR-155, miR-132, miR-3473e, miR-222, and miR-146b showed strong temporal regulation, while miR-3963 was sharply downregulated by bzATP. These DEMs regulate inflammatory pathways, including TNFα and NFκB signaling. We also examined the effect of ladostigil, a neuroprotective agent known to reduce oxidative stress and inflammation. At 8 h post-activation, ladostigil induced upregulation of anti-inflammatory miRNAs, such as miR-27a, miR-27b, and miR-23b. Our findings suggest that miRNA profiles reflect microglial responses to inflammatory cues and that ladostigil modulates these responses. This model of controlled microglial activation offers a powerful tool with which to study inflammation in the aging brain and the progression of neurodegenerative diseases.
小胶质细胞的主要功能是维持大脑内环境稳定。在阿尔茨海默病等神经退行性疾病中，小胶质细胞会导致神经毒性和炎症。在本研究中，我们将新生小鼠原代小胶质细胞培养物暴露于模拟病原体、损伤或毒素的刺激下。用苯甲酰ATP（bzATP）和脂多糖（LPS）处理会引发白细胞介素和趋化因子表达的协同增加。我们分析了激活后3小时和8小时具有统计学意义的差异表达微小RNA（DEM），分别鉴定出33个和57个DEM。值得注意的是，miR-155、miR-132、miR-3473e、miR-222和miR-146b表现出强烈的时间调控，而miR-3963被bzATP急剧下调。这些DEM调节炎症途径，包括TNFα和NFκB信号传导。我们还研究了拉多替吉（一种已知可减少氧化应激和炎症的神经保护剂）的作用。在激活后8小时，拉多替吉诱导抗炎性微小RNA（如miR-27a、miR-27b和miR-23b）上调。我们的研究结果表明，微小RNA谱反映了小胶质细胞对炎症信号的反应，并且拉多替吉可调节这些反应。这种可控的小胶质细胞激活模型为研究衰老大脑中的炎症和神经退行性疾病的进展提供了一个强大的工具。
