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

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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.