Upregulation of C1QC as a Mediator of Blood-Brain Barrier Damage in Type 2 Diabetes Mellitus

The blood-brain barrier (BBB) is a neurovascular structure that safeguards the brain by inhibiting the passage of harmful substances. In individuals with type 2 diabetes mellitus (T2DM), the heightened blood glucose may cause damage to endothelial cells and neurons, increase collagen protein content, and elevate BBB permeability. Although the impact of blood glucose regulation on the structure and function of BBB has been documented, the exact mechanism remains incompletely elucidated. The primary aim of this investigation was to uncover the pivotal dysregulation of specific genes observed within the cerebral microvascular endothelial cells of diabetic patients, with a particular focus on understanding its biological implications in the disruption of the BBB. By integrating bioinformatics analysis, we identified C1QC as a potential upregulated marker. The expression level of C1QC was subsequently verified in both in vivo and in vitro models. Our experiments have discovered that, under diabetic conditions, suppressing C1QC leads to the mitigation of BBB damage. The presence of a high level of C1QC, through its binding to discoidin domain receptor 2 (DDR2), may trigger the activation of its downstream MMP9, a calcium-dependent enzyme that is capable of degrading protein components in the extracellular matrix, consequently leading to the structural and functional disruption of BBB. In summary, the findings of this study indicate that the aberrantly upregulated expression of C1QC may exert deleterious effects on the BBB under diabetes. To alleviate neurological impairments in individuals with T2DM, C1QC may emerge as a promising therapeutic target worthy of further investigation.