Cerebral microthrombi promote focal Cav-1-dependent blood-brain barrier impairment, triggering neuroinflammation and neuronal damage after traumatic brain injury
Year: 2026
Type: preprint
Abstract: Traumatic brain injury (TBI) is frequently accompanied by blood–brain barrier (BBB) dysfunction, yet the microvascular events that initiate barrier failure and secondary neural injury remain poorly understood. Using highly sensitive fluorescent nanoscale tracers, correlative light and electron microscopy, single-cell transcriptomics, and genetic manipulation of Caveolin-1 (Cav-1), we show that BBB leakage after TBI in mice occurs focally at sites of cerebral microthrombus formation. Endothelial cells adjacent to microthrombi remain structurally intact, but exhibit a distinct transcriptional program enriched in both thrombosis- and transcytosis-related genes, including Cav-1. Microthrombi promote Cav-1-dependent transcytosis and size-selective extravasation of blood-borne proteins, exposing the surrounding parenchyma to circulating factors and inducing focal microglia activation and neuronal damage in vivo. In human induced pluripotent stem cell-derived neurons, these proteins directly impaired neuronal structure and network function. Genetic deletion of Cav-1 markedly reduces microthrombus-associated BBB leakage, immune-cell diapedesis, microglial activation and neuronal loss, whereas endothelial re-expression of Cav-1 using AAVs restores leakage. Human TBI data reveal early dynamic coagulation dysregulation associated with adverse clinical outcome, focal cerebral vascular injury and endothelial transcriptional signatures consistent with reduced barrier integrity and increased caveolae-associated transport. Together, these findings identify cerebral microthrombi as focal sites of Cav-1-dependent BBB dysfunction and establish pathological endothelial transcytosis as a mechanistic link between post-traumatic microvascular thrombosis, blood protein extravasation and secondary neuronal injury. Targeting Cav-1-dependent transcytosis may therefore provide a strategy to limit pathological BBB permeability and secondary injury after TBI. Abstract Figure Graphical Abstract
Authors: A. Wehn, M. Schifferer, J. Shrouder, A. Talukdar, M. Louessard, M. Abioui-Mourgues, V. J. Boide-Trujillo, G-M Calandra, B. Groschup, M. Reid, J. Oberhauser, U. Mamrak, M-L. Fleury, P. Marie, F. Moschogiannaki, A. Gerschmann, S. Yoshimura, S. Niedermeyer, T. Weig, N. Terpolilli, L. Dauphinot, A. Yang, A. Klymchenko, F. Ringel, D. Vivien, N. Plesnila, I. Khalin
Institutions: LMU Klinikum, Institut für Schlaganfall- und Demenzforschung, Ludwig-Maximilians-Universität München, German Center for Neurodegenerative Diseases, Munich Cluster for Systems Neurology, University of Copenhagen, Normandie Université, Physiopathologie et imagerie des troubles neurologiques, Université de Caen Normandie, Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Leipzig University, University of California, San Francisco, Technical University of Munich, Nihon University, University Hospital Heidelberg, Centre National de la Recherche Scientifique, Inserm, Cyceron
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7214748566