VASCULAR DYSREGULATION AND BLOOD-BRAIN BARRIER IMPAIRMENT IN A MURINE MODEL OF NEURODEGENERATION

Neurodegenerative disorders (NDs) encompass a heterogeneous group of conditions characterized by progressive loss of neuronal structure and function. While traditionally attributed to intrinsic neuronal dysfunction, emerging evidence suggests that vascular abnormalities may play a contributory role in the pathogenesis of several NDs. However, the extent to which vascular anomalies are implicated across neurodegenerative conditions remains poorly understood and insufficiently characterized. To address this gap, we investigated vascular alterations in Lafora Disease (LD), a rare and fatal form of early-onset neurodegeneration classified under Progressive Myoclonus Epilepsies. LD is typically marked by seizures, cognitive decline, and motor dysfunction. Using a well-established murine model of LD, we examined systemic vascular parameters through blood pressure, flow rate and heart rate analysis. We also focused towards studying the cerebral vascular parameters through computed-tomography-based imaging of brain, blood-brain-barrier (BBB) markers and permeability assessment. Our findings reveal significant cardiovascular anomalies, including hypertension, reduced blood flow rate, bradycardia, and increased vascular permeability. Whole-brain imaging further uncovered structural deformities in cerebral vasculature. We observed dysregulation of genes associated with vascular development and maintenance in our whole brain RNA-seq, alongside compromised integrity of BBB. Ultrastructural analysis also unveiled disintegrated endothelial glycocalyx which could be a primary cause of the BBB impairment. These results underscore a potentially underappreciated vascular component in LD pathophysiology and suggest that systemic vascular dysfunction may contribute to disease progression. By elucidating these vascular signatures, our study opens new avenues for therapeutic intervention and highlights the importance of monitoring extracerebral biomarkers in the management of neurodegenerative disorders.