Jia Ruxue, Solé-Guardia Gemma, Verweij Vivienne, Snabel Jessica M, Geenen Bram, Tuladhar Anil Man, Kleemann Robert, Kiliaan Amanda J, Wiesmann Maximilian
Department of Medical Imaging, Anatomy, Radboud University Medical Center, Donders Institute for Brain, Cognition & Behavior, Center for Medical Neuroscience, Preclinical Imaging Center PRIME, Radboud Alzheimer Center, Radboudumc, 6525 EZ Nijmegen, The Netherlands.
Department of Neurology, Research Institute for Medical Innovation, Donders Institute for Brain, Cognition and Behavior, Radboudumc, 6525 GA Nijmegen, The Netherlands.
Int J Mol Sci. 2025 Jul 12;26(14):6706. doi: 10.3390/ijms26146706.
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.
血脑屏障（BBB）功能障碍是脑小血管病（cSVD）的一个标志。本研究旨在确定一种复制BBB损伤并具有关键cSVD风险因素的小鼠模型。将易患肥胖症和高血压的转基因db/db和LDLr.Leiden小鼠与C57BL/6J对照小鼠进行比较。使用动态对比增强磁共振成像（DCE-MRI）和荧光素钠（NaFl）评估BBB渗漏；通过MRI测量脑血流量（CBF）。通过血浆检测测量血脂异常和血管炎症。用免疫组织化学和聚合酶链反应评估紧密连接完整性、内皮功能障碍（葡萄糖转运蛋白1，GLUT-1）和神经炎症。两种转基因模型均出现伴有高胰岛素血症的肥胖表型，但只有LDLr.Leiden小鼠表现出类似人类的血脂异常。当喂食高脂饮食（HFD）或HFD加胆固醇时，LDLr.Leiden小鼠表现出CBF降低、内皮功能障碍（GLUT-1降低）、血管炎症升高（细胞间黏附分子-1、血管细胞黏附分子-1、S-选择素）以及BBB渗漏，DCE-MRI和NaFl证明了这一点，同时紧密连接蛋白1（ZO-1）和闭合蛋白5表达降低。相比之下，db/db小鼠表现出内皮功能障碍但无BBB渗漏。仅在LDLr.Leiden组中观察到神经炎症（离子钙结合衔接分子1，IBA-1；胶质纤维酸性蛋白，GFAP），这与BBB破坏一致。这些发现表明，LDLr.Leiden小鼠而非db/db小鼠是研究cSVD中BBB功能障碍的一个有前景的转化模型，为疾病机制提供了见解，并为治疗开发提供了一个平台。
