Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.
China National Clinical Research Center for Neurological Diseases, Beijing, 100070, China.
Cell Mol Neurobiol. 2023 Dec 17;44(1):5. doi: 10.1007/s10571-023-01435-4.
Traumatic brain injury (TBI) is a serious public health problem worldwide, which could lead to an extremely high percentage of mortality and disability. Current treatment strategies mainly concentrate on neuronal protection and reconstruction, among them, exogenous neural stem cell (NSC) transplantation has long been regarded as the most effective curative treatment. However, due to secondary trauma, transplant rejection, and increased incidence of brain malignant tumor, a non-invasive therapy that enhanced endogenous neurogenesis was more suitable for TBI treatment. Our previous work has shown that miR-132 overexpression could improve neuronal differentiation of NSCs in vitro and in vivo. So, we engineered a new kind of AAV vector named AAV-PHP.eB which can transfect brain parenchyma through intravenous injection to overexpress miR-132 in brain after TBI. We found that miR-132 overexpression could reduce impact volume, promote neurogenesis in the dentate gyrus (DG), accelerate neuroblast migrating into the impact cortex, ameliorate microglia-mediated inflammatory reaction, and ultimately restore learning memory function. Our results revealed that AAV-PHP.eB-based miR-132 overexpression could improve endogenous tissue repairment and release clinical symptoms after traumatic brain injury. This work would provide a new therapeutic strategy for TBI treatment and other neurological disorders characterized by markable neuronal loss and memory impairment. miR-132 overexpression accelerates endogenous neurogenesis and releases TBI-induced tissue repairment and memory impairment. Controlled cortical impact onto the cortex would induce serious cortical injury and microglia accumulation in both cortex and hippocampus. Moreover, endogenous neuroblast could migrate around the injury core. miR-132 overexpression could accelerate neuroblast migration toward the injury core and decreased microglia accumulation in the ipsilateral cortex and hippocampus. miR-132 could be a suitable target on neuroprotective therapy after TBI.
创伤性脑损伤（TBI）是全球范围内一个严重的公共卫生问题，可导致极高的死亡率和残疾率。目前的治疗策略主要集中在神经元保护和重建上，其中，外源性神经干细胞（NSC）移植长期以来被认为是最有效的治疗方法。然而，由于二次创伤、移植排斥和脑恶性肿瘤发病率增加，一种增强内源性神经发生的非侵入性治疗方法更适合 TBI 治疗。我们之前的工作表明，miR-132 的过表达可以体外和体内增强 NSCs 的神经元分化。因此，我们设计了一种新型的 AAV 载体，命名为 AAV-PHP.eB，它可以通过静脉注射转染脑实质，在 TBI 后在脑中过表达 miR-132。我们发现，miR-132 的过表达可以减少冲击体积，促进齿状回（DG）中的神经发生，加速神经母细胞迁移到冲击皮层，改善小胶质细胞介导的炎症反应，最终恢复学习记忆功能。我们的结果表明，基于 AAV-PHP.eB 的 miR-132 过表达可以改善创伤性脑损伤后的内源性组织修复和临床症状释放。这项工作将为 TBI 治疗和其他以明显神经元丧失和记忆障碍为特征的神经退行性疾病提供新的治疗策略。miR-132 的过表达加速内源性神经发生并释放 TBI 诱导的组织修复和记忆损伤。皮质控制冲击会在皮质和海马体中引起严重的皮质损伤和小胶质细胞聚集。此外，内源性神经母细胞可以在损伤核心周围迁移。miR-132 的过表达可以加速神经母细胞向损伤核心的迁移，并减少同侧皮质和海马体中小胶质细胞的聚集。miR-132 可能是 TBI 后神经保护治疗的一个合适靶点。
