Department of Anatomy, Physiology and Pharmacology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK S7N 5E5, Canada.
Department of Medical Imaging, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 0W8, Canada.
Int J Mol Sci. 2021 Aug 20;22(16):9005. doi: 10.3390/ijms22169005.
Brain injury/concussion is a growing epidemic throughout the world. Although evidence supports association between traumatic brain injury (TBI) and disturbance in brain glucose metabolism, the underlying molecular mechanisms are not well established. Previously, we reported the release of cellular prion protein (PrPc) from the brain to circulation following TBI. The PrPc level was also found to be decreased in insulin-resistant rat brains. In the present study, we investigated the molecular link between PrPc and brain insulin resistance in a single and repeated mild TBI-induced mouse model. Mild TBI was induced in mice by dropping a weight (~95 g at 1 m high) on the right side of the head. The procedure was performed once and thrice (once daily) for single (SI) and repeated induction (RI), respectively. Micro PET/CT imaging revealed that RI mice showed significant reduction in cortical, hippocampal and cerebellum glucose uptake compared to SI and control. Mice that received RI also showed significant motor and cognitive deficits. In co-immunoprecipitation, the interaction between PrPc, flotillin and Cbl-associated protein (CAP) observed in the control mice brains was disrupted by RI. Lipid raft isolation showed decreased levels of PrPc, flotillin and CAP in the RI mice brains. Based on observation, it is clear that PrPc has an interaction with CAP and the dislodgment of PrPc from cell membranes may lead to brain insulin resistance in a mild TBI mouse model. The present study generated a new insight into the pathogenesis of brain injury, which may result in the development of novel therapy.
脑损伤/脑震荡是全球范围内日益严重的流行疾病。尽管有证据表明创伤性脑损伤（TBI）与脑葡萄糖代谢紊乱之间存在关联，但潜在的分子机制尚未得到充分证实。此前，我们曾报道过 TBI 后细胞朊蛋白（PrPc）从大脑释放到循环中的现象，并且还发现胰岛素抵抗大鼠大脑中的 PrPc 水平降低。在本研究中，我们在单次和重复轻度 TBI 诱导的小鼠模型中研究了 PrPc 与脑胰岛素抵抗之间的分子联系。通过将约 95 克重的重物（从 1 米高处）落在右侧头部来诱导小鼠轻度 TBI。单次（SI）和重复（RI）诱导分别进行一次和三次（每天一次）。微 PET/CT 成像显示，与 SI 和对照组相比，RI 小鼠的皮质、海马和小脑葡萄糖摄取明显减少。接受 RI 的小鼠还表现出明显的运动和认知缺陷。在共免疫沉淀中，对照组小鼠大脑中观察到的 PrPc、 flotillin 和 Cbl 相关蛋白（CAP）之间的相互作用被 RI 破坏。脂质筏分离显示 RI 小鼠大脑中的 PrPc、 flotillin 和 CAP 水平降低。根据观察结果，很明显 PrPc 与 CAP 相互作用，PrPc 从细胞膜上脱离可能导致轻度 TBI 小鼠模型中的脑胰岛素抵抗。本研究为脑损伤的发病机制提供了新的见解，可能为新疗法的开发提供依据。
