Cerebral microthrombi promote focal Cav-1-dependent blood-brain barrier impairment, triggering neuroinflammation and neuronal damage after traumatic brain injury

Traumatic brain injury (TBI) often leads to blood-brain barrier (BBB) dysfunction, but the specific microvascular events causing this failure and subsequent neural damage are not well understood. Researchers employed advanced techniques such as fluorescent nanoscale tracers, correlative light and electron microscopy, single-cell transcriptomics, and genetic manipulation of Caveolin-1 (Cav-1) to shed light on this issue.

Their findings reveal that BBB leakage occurs in specific areas due to the formation of cerebral microthrombi. While endothelial cells near these microthrombi remain structurally intact, they display a unique transcriptional profile highlighting thrombosis- and transcytosis-related genes, including Cav-1.

Microthrombi facilitate Cav-1-dependent transcytosis and selective transport of blood-borne proteins into the brain's parenchyma, which exposes neural tissues to circulating factors. This process triggers focal microglia activation and neuronal damage in living organisms. In human stem cell-derived neurons, the same proteins impair neuronal structure and network function.

Blocking Cav-1 via genetic deletion markedly reduces microthrombus-associated BBB leakage, immune-cell migration, microglial activation, and neuronal loss. Conversely, re-expressing Cav-1 in endothelial cells using AAVs restores leakage. Analysis of human TBI data indicates early coagulation dysregulation associated with poor clinical outcomes, focal cerebral vascular injury, and endothelial transcriptional signatures indicative of diminished barrier integrity and increased caveolae-associated transport.

Overall, these studies pinpoint cerebral microthrombi as focal points of Cav-1-dependent BBB dysfunction, establishing pathological endothelial transcytosis as a key mechanism linking post-traumatic microvascular thrombosis, blood protein extravasation, and secondary neuronal injury. Targeting Cav-1-dependent transcytosis could therefore serve as a therapeutic strategy to mitigate pathological BBB permeability and secondary injury following TBI.