Endothelial Genetic Deletion of CD147 Induces Changes in the Dual Function of the BBB and Is Implicated in Alzheimer's Disease

Background: The blood brain barrier (BBB) is a specialized and indispensable structure in brain blood vessels that is damaged during Alzheimer’s disease (AD). CD147 is expressed on the BBB and possibly engaged in the AD pathological process. Thus, our study aimed to provide a better understanding of the roles of CD147 in BBB function in health and in neurodegenerative disease. Methods: We measured CD147 expression in mouse brains via immunofluorescence and immunohistochemical staining. We constructed endothelial-specific CD147 knockout mice and evaluated the BBB integrity of different ages by dye permeability both in vivo and in vitro. To comprehensively study the transcriptomic changes of CD147 deficiency, we performed RNA sequencing on isolated primary brain endothelial cells (BECs) as well as a range of database analyses. Many meaningful altered genes were also validated via RT-qPCR and/or western blotting. Finding: We validate that CD147 is exclusively expressed in BECs under normal circumstance, and its expression decreases with age. We demonstrate that CD147 deletion not only impairs BBB integrity by inducing expression of tight junction molecules, but also regulates transporter on the BBB. This study also shows that CD147 regulates expression of genes associated with neurodegenerative diseases, particularly AD. Interpretation: Our findings demonstrate the roles of CD147 on the BECs, which may promote the design of future experimental investigations and the mechanistic understanding of neurodegenerative diseases. Together, we illustrate transcriptomic changes in CD147-deficient BECs that are complicated yet meaningful. Funding: This work was supported by the National Key Research and Development Program of China (2019YFC1316303). Declaration of Interests: The all authors declare that no conflicts of interest exist. Ethics Approval Statement: Animal experiments were approved by the Animal Care and Use Committee of the Fourth Military Medical University.