The Breakdown of Neurovascular Barriers: Molecular Mechanisms of Tight Junction Dysfunction

The central nervous system (CNS) relies on tightly regulated barriers to maintain homeostasis and protect neural tissue from blood-borne toxins, pathogens, and inflammatory mediators. Tight junctions (TJs) are critical components of the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB), forming selective paracellular seals that regulate molecular trafficking. These structures comprise transmembrane proteins and cytoplasmic scaffolding proteins, which anchor TJs to the actin cytoskeleton. The spatial organization and function of TJs are dynamically regulated by calcium-dependent signaling, phosphorylation events, and G-protein-mediated pathways, which govern their assembly, disassembly, and response to physiological and pathological stimuli. The integrity of TJ complexes is particularly vulnerable to disruption in neurological disorders. Dysregulation of key TJ proteins has been implicated in neurodegenerative diseases, neuroinflammation, and CNS injury, leading to barrier permeability defects that exacerbate disease progression. Emerging therapeutic strategies aim to modulate TJs to stabilize barrier integrity and to mitigate pathology. This review examines the molecular architecture and regulatory mechanisms of TJ complexes, their dysfunction in disease states, and the translational potential of targeting them for therapy. A detailed understanding of TJ dynamics is essential for developing strategies to restore barrier function in neurological disorders.