Liu Kai, Fan Di, Wu Hai-Peng, Hu Xiao-Yi, He Qiu-Li, Wu Xin-Miao, Shi Cui-Na, Yang Jian-Jun, Ji Mu-Huo
Department of Anesthesiology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Aging Cell. 2025 Jul 7:e70167. doi: 10.1111/acel.70167.
Microglia-mediated neuroinflammation has been shown to exert an important effect on the progression of a growing number of neurodegenerative disorders. Prolonged exposure to detrimental stimuli leads to a state of progressive activation and aging-related features in microglia (also termed as senescent microglia). However, the mechanisms by which senescent microglia contribute to neuroinflammation-induced cognitive dysfunction remain to be elucidated. Here, we developed a mouse model of neuroinflammation induced by lipopolysaccharides at 0.5 mg/kg for 7 consecutive days. To evaluate cognitive function, C57BL/6J mice were employed and subjected to a series of behavioral assessments, including the open field, Y-maze, and novel object recognition tests. Employing single-cell RNA sequencing technology, we have delved into the differential expressions of RNA within microglia. Furthermore, to investigate anatomic and physiological alterations of pyramidal neurons, we utilized Golgi staining and whole-cell patch-clamp recordings, respectively. Validation of our results in protein expression was performed using western blotting and immunofluorescence. We specifically identified senescent microglia with a high expression of p16 and observed that microglia in the hippocampal CA1 region of the model exhibited signatures of elevated phagocytosis and senescence. A senolytic by ABT-737 treatment alleviated the production of senescence-associated secretory phenotypes, the accumulation of senescent microglia, and the microglial hyperphagocytosis of excitatory synapses following LPS exposures. This treatment also restored reduced excitatory synaptic transmission, impaired long-term potentiation, and cognitive function in the model. These results indicate that reducing senescent microglia may potentially serve as a therapeutic approach to prevent neuroinflammation-related cognitive dysfunction.
小胶质细胞介导的神经炎症已被证明对越来越多的神经退行性疾病的进展具有重要影响。长期暴露于有害刺激会导致小胶质细胞进入渐进性激活状态并出现与衰老相关的特征（也称为衰老小胶质细胞）。然而，衰老小胶质细胞导致神经炎症诱导的认知功能障碍的机制仍有待阐明。在此，我们建立了一种小鼠神经炎症模型，通过连续7天腹腔注射0.5mg/kg脂多糖诱导。为了评估认知功能，我们选用C57BL/6J小鼠并对其进行了一系列行为学评估，包括旷场试验、Y迷宫试验和新物体识别试验。利用单细胞RNA测序技术，我们深入研究了小胶质细胞内RNA的差异表达。此外，为了研究锥体神经元的解剖学和生理学改变，我们分别采用了高尔基染色和全细胞膜片钳记录技术。我们使用蛋白质免疫印迹和免疫荧光对结果进行了蛋白质表达验证。我们通过p16高表达特异性鉴定了衰老小胶质细胞，并观察到模型小鼠海马CA1区的小胶质细胞表现出吞噬作用增强和衰老的特征。ABT-737处理的衰老细胞溶解剂减轻了衰老相关分泌表型的产生、衰老小胶质细胞的积累以及脂多糖暴露后兴奋性突触的小胶质细胞过度吞噬。这种处理还恢复了模型小鼠中降低的兴奋性突触传递、受损的长时程增强和认知功能。这些结果表明，减少衰老小胶质细胞可能是预防神经炎症相关认知功能障碍的一种潜在治疗方法。
