3D Models of the Blood-Brain Barrier for Studying Trauma-Induced Cerebral and Systemic Injuries

摘要 创伤性脑损伤(TBI)和阿尔茨海默病(AD)是两种破坏性的神经疾病，具有 复杂的关系。研究表明，有中度或重度脑外伤病史的患者有两个 与那些没有头部损伤病史的人相比，患AD的风险增加了四倍。这个 两种疾病之间的机制联系还没有被很好地理解。两种疾病都表现为脑血管疾病 功能障碍，这将是脑外伤和随后的血管发展之间的因果联系 痴呆症和阿尔茨海默病。颅脑损伤患者最初遭受急性损伤，这破坏了关节结构的完整性 大脑和脑血管系统。这种破坏会导致血脑屏障(BBB)的进一步破坏。 脑外伤后尸检发现弥漫性淀粉样β蛋白(A-β)斑块 受伤。看来，脑外伤所致的神经血管损伤可以加速生产和血管周围。 淀粉样β蛋白(Aβ)积聚，导致血脑屏障受损，引发有害饲料- 向前循环。然而，目前还不清楚是什么机制导致了Aβ在脑损伤中的积聚。我们假设 血管渗漏和暴露于血浆因子导致神经元和 Aβ从神经血管壁龛的清除减少。在本补充文件中，我们提出了一项补充 研究血管破裂对神经细胞功能的继发性影响并确定 血浆因子对脑器质中神经细胞产生A-β的影响我们 将在分离的有机体和在血管界面共培养的有机体中进行这些实验。 我们将确定颅脑损伤患者的血浆因素如何影响Aβ产生的HIPSC来源的神经元。我们会 此外，还建立了由血运脑器组成的血脑屏障模型，并评估了血管的作用。 Aβ在血脑屏障周围沉积和积聚的功能障碍。该项目的成功将为 在TBI和AD启动之间的机械联系中的重要信息，并将有许多 对未来预防脑外伤的神经血管工程方法和治疗发展的启示 诱发性AD。

Abstract Traumatic brain injury (TBI) and Alzheimer's disease (AD) are two devastating neurological disorders with a complex relationship. Studies have shown that patients with a history of moderate or severe TBI have a two to four-fold increased risk of developing AD compared to those with no history of head injury. The mechanistic link between two disorders is not well understood. Both diseases show cerebrovascular dysfunction, which would be a causal link between TBI and the subsequent development of vascular dementia and AD. Patients with TBI suffer initial acute injuries, which disrupts the structural integrity of the brain and brain vasculature. Such disruption leads to further breakdown of the blood brain barrier (BBB). Studies of postmortem brains of TBI showed diffuse amyloid beta (Aβ) plaques in autopsies after acute injuries. It appears that TBI-induced neurovascular injuries could accelerate production and perivascular accumulation of amyloid-beta (Aβ), leading to blood brain barrier damage and inducing a deleterious feed- forward loop. However, it is still unclear which mechanisms lead to Aβ accumulation in TBI. We hypothesize that vascular leakage and exposure to plasma factors induce the increased production of Aβ in neurons and decreased clearance of Aβ from neurovascular niche. In this supplement, we propose a complementary project to study the consequent effect of vascular disruption on neuronal cell function and identify the role of plasma factors on Aβ production from neuronal cells in brain organoids we differentiation from hiPSCs. We will perform these experiments in isolated organoids and in organoids co-cultured at the vascular interface. We will identify how plasma factors of TBI patients affect Aβ production hiPSC-derived neurons. We will also establish a BBB model comprised of vascularized brain organoids and evaluate the role of vascular dysfunction on Aβ deposition and accumulation around the BBB. The success of the project will provide important information in mechanistic link between the TBI and initiation of AD, and will have numerous implications in future neurovascular engineering approaches and therapeutic development to prevent TBI induced AD.