EARLY BLOOD–BRAIN BARRIER DYSFUNCTION AND CENTRAL-TO-PERIPHERAL Α-SYNUCLEIN SPREAD IN EXPERIMENTAL PARKINSON’S DISEASE

In Parkinson’s disease (PD), blood–brain barrier (BBB) dysfunction is increasingly recognized as a key pathological contribution; however, the underlying mechanisms and temporal dynamics remain poorly understood. In particular, the role of α-synuclein (α-Syn) in BBB pathology, and its involvement in central-to-peripheral α-Syn propagation has not been examined. Oligomeric α-Syn species are considered particularly toxic in PD due to their small size and high solubility. Sprague–Dawley rats received bilateral infusions of exogenous human α-synuclein oligomers (H-αSynOs) or vehicle into the substantia nigra pars compacta (SNpc). Rats were euthanized at 1-month (asymptomatic) or 3-month (symptomatic) post-infusion for serum, colon, and brain collection. BBB alterations in the SNpc were assessed by immunofluorescence (IF) analysis of tight junction proteins and BBB cellular components, including endothelial cells, pericytes and astrocytes. Central-to-peripheral α-Syn spreading was evaluated by IF quantification of phosphorylated α-Syn (p-α-Syn) in the SNpc and distal colon, and by ELISA measurement of circulating oligomeric α-Syn. Fecal microbiota composition was also analyzed to assess peripheral alterations.
Preliminary results indicated that 1-month after surgery, H-αSynO-infused rats exhibited reduced SNpc levels of PECAM-1 and ZO-1 compared to controls, consistent with early BBB alterations. These changes were no longer evident at 3-month post-infusion; however, increased ZO-1/PECAM-1 colocalization was observed relative to controls. Notably, circulating oligomeric α-Syn levels were elevated as early as 1-month post-infusion and were associated with increased p-α-Syn expression in the colon. Overall, these findings suggest that α-Syn pathology promotes early, dynamic BBB remodeling, that facilitate progressive central-to-peripheral α-Syn leakage and pathological spreading.