Tian Zhicheng, Cao Zixuan, Yang Erwan, Li Juan, Liao Dan, Wang Fei, Wang Taozhi, Zhang Zhuoyuan, Zhang Haofuzi, Jiang Xiaofan, Li Xin, Luo Peng
Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, China.
The Sixth Regiment, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi Province, China.
Neural Regen Res. 2023 Dec;18(12):2711-2719. doi: 10.4103/1673-5374.374654.
The cumulative damage caused by repetitive mild traumatic brain injury can cause long-term neurodegeneration leading to cognitive impairment. This cognitive impairment is thought to result specifically from damage to the hippocampus. In this study, we detected cognitive impairment in mice 6 weeks after repetitive mild traumatic brain injury using the novel object recognition test and the Morris water maze test. Immunofluorescence staining showed that p-tau expression was increased in the hippocampus after repetitive mild traumatic brain injury. Golgi staining showed a significant decrease in the total density of neuronal dendritic spines in the hippocampus, as well as in the density of mature dendritic spines. To investigate the specific molecular mechanisms underlying cognitive impairment due to hippocampal damage, we performed proteomic and phosphoproteomic analyses of the hippocampus with and without repetitive mild traumatic brain injury. The differentially expressed proteins were mainly enriched in inflammation, immunity, and coagulation, suggesting that non-neuronal cells are involved in the pathological changes that occur in the hippocampus in the chronic stage after repetitive mild traumatic brain injury. In contrast, differentially expressed phosphorylated proteins were mainly enriched in pathways related to neuronal function and structure, which is more consistent with neurodegeneration. We identified N-methyl-D-aspartate receptor 1 as a hub molecule involved in the response to repetitive mild traumatic brain injury , and western blotting showed that, while N-methyl-D-aspartate receptor 1 expression was not altered in the hippocampus after repetitive mild traumatic brain injury, its phosphorylation level was significantly increased, which is consistent with the omics results. Administration of GRP78608, an N-methyl-D-aspartate receptor 1 antagonist, to the hippocampus markedly improved repetitive mild traumatic brain injury-induced cognitive impairment. In conclusion, our findings suggest that N-methyl-D-aspartate receptor 1 signaling in the hippocampus is involved in cognitive impairment in the chronic stage after repetitive mild traumatic brain injury and may be a potential target for intervention and treatment.
重复性轻度创伤性脑损伤造成的累积损伤可导致长期神经退行性变，进而引起认知障碍。这种认知障碍被认为是由海马体损伤所致。在本研究中，我们使用新颖物体识别测试和莫里斯水迷宫测试，在重复性轻度创伤性脑损伤6周后的小鼠中检测到了认知障碍。免疫荧光染色显示，重复性轻度创伤性脑损伤后海马体中p-tau表达增加。高尔基染色显示，海马体中神经元树突棘的总密度以及成熟树突棘的密度显著降低。为了探究海马体损伤导致认知障碍的具体分子机制，我们对有或无重复性轻度创伤性脑损伤的海马体进行了蛋白质组学和磷酸化蛋白质组学分析。差异表达的蛋白质主要富集于炎症、免疫和凝血过程，这表明非神经元细胞参与了重复性轻度创伤性脑损伤慢性期海马体发生的病理变化。相比之下，差异表达的磷酸化蛋白质主要富集于与神经元功能和结构相关的通路，这与神经退行性变更为一致。我们将N-甲基-D-天冬氨酸受体1鉴定为参与重复性轻度创伤性脑损伤反应的枢纽分子，蛋白质免疫印迹法显示，虽然重复性轻度创伤性脑损伤后海马体中N-甲基-D-天冬氨酸受体1的表达未改变，但其磷酸化水平显著升高，这与组学结果一致。向海马体注射N-甲基-D-天冬氨酸受体1拮抗剂GRP78608可显著改善重复性轻度创伤性脑损伤诱导的认知障碍。总之，我们的研究结果表明，海马体中的N-甲基-D-天冬氨酸受体1信号传导参与了重复性轻度创伤性脑损伤慢性期的认知障碍，可能是干预和治疗的潜在靶点。
