Exogenous IFNα Impairs Neural Communication by Disrupting Endothelial Mitochondrial Function at the Blood-Brain Barrier 2258446

Abstract Introduction Type I interferon alpha (IFNα) is essential to maintain immune surveillance, but, when abnormally elevated, drives neuroinflammation, blood-brain barrier (BBB) breakdown, and neuropsychiatric dysfunction. However, the mechanisms underlying IFNα-induced brain homeostatic imbalance remain poorly understood. Methods We investigated the impact of IFNα on BBB integrity by intravenously administering IFNα to young adult mice. Mice received daily treatment for 4 days, followed by the assessment of vascular leakage using FITC—dextran and tight junction Claudin-5 (CLDN5) continuity. The consequence of vascular leakage is analyzed by astrocytic morphology, and interferon-stimulated gene (ISG) expression in the hippocampus. Endothelial mitochondria were examined for number and NADPH oxidase 2 (Nox2) levels, with IFNAR1 blockade used to test signaling involvement. Neuronal activity in hippocampal CA3 was quantified by c-fos immunostaining, and ongoing studies include flow cytometry of macrophage accumulation and in vivo two-photon imaging of vascular—immune—neural interactions. Results IFNα-treated mice exhibited multiple vascular leakage sites, indicating compromised BBB stability. Capillary analysis showed disrupted CLDN5 junctions, astrocytic end-feet retraction, and significant hippocampal ISG upregulation. Endothelial mitochondria displayed reduced abundance and elevated Nox2 expression that is reversed by IFNAR1 blockade, implicating endothelial IFNα—IFNAR1 signaling in mitochondrial stress. Consequently, neuronal activation was elevated in hippocampal CA3 neurons, suggesting enhanced hippocampal input relevant to memory processing. Conclusion These findings demonstrate that IFNα induces endothelial mitochondrial stress to disrupt BBB integrity, establishing a mechanistic link between neuroinflammation, vascular dysfunction, and altered brain immune—neuronal dynamics. Funding Source NIH P50MH112491 Topic Categories Neuroimmunology (NEUR)