Identification and Characterization of a Translational Mouse Model for Blood–Brain Barrier Leakage in Cerebral Small Vessel Disease

Blood-brain barrier (BBB) dysfunction is a hallmark of cerebral small vessel disease (cSVD). This study aimed to identify a mouse model that replicates BBB impairment and shares key cSVD risk factors. Transgenic db/db and LDLr^-/-.Leiden mice, both prone to obesity and hypertension, were compared to C57BL/6J controls. BBB leakage was assessed using DCE-MRI and sodium fluorescein (NaFl); cerebral blood flow (CBF) by MRI. Dyslipidemia and vascular inflammation were measured by plasma tests. Tight junction integrity, endothelial dysfunction (glucose transporter 1, GLUT-1) and neuroinflammation were evaluated with immunohistochemistry and PCR. Both transgenic models developed an obese phenotype with hyperinsulinemia, but only LDLr^-/-.Leiden mice showed human-like dyslipidemia. When fed a high-fat diet (HFD) or HFD plus cholesterol, LDLr^-/-.Leiden mice showed reduced CBF, endothelial dysfunction (lowered GLUT-1), elevated vascular inflammation (ICAM-1, VCAM-1, S-selectin), and BBB leakage, as evidenced by DCE-MRI and NaFl, together with reduced ZO-1 and claudin-5 expression. Contrastingly, db/db mice showed endothelial dysfunction without BBB leakage. Neuroinflammation (IBA-1, GFAP) was observed only in LDLr^-/-.Leiden groups, consistent with BBB disruption. These findings indicate that LDLr^-/-.Leiden mice, but not db/db mice, are a promising translational model for studying BBB dysfunction in cSVD, offering insights into disease mechanisms and a platform for therapeutic development.