Center for Neurodegeneration and Regeneration, Zilkha Neurogenetic Institute, Room: 241, 1501 San Pablo Street, Los Angeles, CA, 90033, USA.
Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
Acta Neuropathol Commun. 2021 Apr 23;9(1):74. doi: 10.1186/s40478-021-01178-7.
Traumatic brain injury (TBI) is considered as the most robust environmental risk factor for Alzheimer's disease (AD). Besides direct neuronal injury and neuroinflammation, vascular impairment is also a hallmark event of the pathological cascade after TBI. However, the vascular connection between TBI and subsequent AD pathogenesis remains underexplored.
In a closed-head mild TBI (mTBI) model in mice with controlled cortical impact, we examined the time courses of microvascular injury, blood-brain barrier (BBB) dysfunction, gliosis and motor function impairment in wild type C57BL/6 mice. We also evaluated the BBB integrity, amyloid pathology as well as cognitive functions after mTBI in the 5xFAD mouse model of AD.
mTBI induced microvascular injury with BBB breakdown, pericyte loss, basement membrane alteration and cerebral blood flow reduction in mice, in which BBB breakdown preceded gliosis. More importantly, mTBI accelerated BBB leakage, amyloid pathology and cognitive impairment in the 5xFAD mice.
Our data demonstrated that microvascular injury plays a key role in the pathogenesis of AD after mTBI. Therefore, restoring vascular functions might be beneficial for patients with mTBI, and potentially reduce the risk of developing AD.
创伤性脑损伤（TBI）被认为是阿尔茨海默病（AD）最强有力的环境风险因素。除了直接的神经元损伤和神经炎症，血管损伤也是 TBI 后病理级联反应的标志事件。然而，TBI 与随后的 AD 发病机制之间的血管联系仍未得到充分探索。
在具有皮质冲击控制的小鼠闭合性头部轻度 TBI（mTBI）模型中，我们检查了野生型 C57BL/6 小鼠中小血管损伤、血脑屏障（BBB）功能障碍、神经胶质增生和运动功能障碍的时间过程。我们还评估了 mTBI 后 5xFAD 小鼠 AD 模型中的 BBB 完整性、淀粉样蛋白病理和认知功能。
mTBI 诱导了小鼠的微血管损伤，伴有 BBB 破裂、周细胞丧失、基底膜改变和脑血流减少，其中 BBB 破裂先于神经胶质增生。更重要的是，mTBI 加速了 5xFAD 小鼠的 BBB 渗漏、淀粉样蛋白病理和认知障碍。
我们的数据表明，微血管损伤在 mTBI 后 AD 的发病机制中起关键作用。因此，恢复血管功能可能对 mTBI 患者有益，并可能降低发展为 AD 的风险。
