Journal Article Epublish
PubMed: 40724955 DOI: 10.3390/ijms26146706
Identification and Characterization of a Translational Mouse Model for Blood-Brain Barrier Leakage in Cerebral Small Vessel Disease.
Int J Mol Sci 26(14)
Authors: Ruxue Jia, Gemma Solé-Guardia, Vivienne Verweij, Jessica M Snabel, Bram Geenen, Anil Man Tuladhar, Robert Kleemann, Amanda J Kiliaan, Maximilian Wiesmann
Affiliations
- 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.
- Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands.
Abstract
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.
MeSH
Blood-Brain Barrier, Blood, Brain, Cerebral Small Vessel Diseases