Tight Junction Regulation in Blood–Brain Barrier Integrity and Neurological Diseases

Export Through controlling the flow of molecules between the circulation and the brain, the blood–brain barrier (BBB) maintains homeostasis in the central nervous system (CNS). Crucial for sealing endothelial cell connections and maintaining BBB integrity are tight junctions (TJs), which are composed of transmembrane proteins (occludin, claudins, and junctional adhesion molecules). This review critically examines the molecular structure and regulatory processes of TJs within the BBB, emphasizing their dynamic modulation in neurological disorders such as neurodegenerative, neuroinflammatory, autoimmune, cerebrovascular, neuropsychiatric, neurodevelopmental, neuro-oncological, and neurovascular disorders. Emphasis is placed on how TJ disruption contributes to barrier breakdown and disease progression, with insights into key signaling pathways and regulatory networks, including Wnt/β-catenin, CmPn/CmP steroid signaling networks, phosphorylation cascades, matrix metalloproteinase activities, microRNA regulation, and the gut–brain axis. Recent advances in elucidating TJ protein interactions and their regulatory modulators have identified promising therapeutic targets for restoring BBB function and attenuating neuroinflammatory processes. Furthermore, innovative approaches for precisely regulating TJs to enhance drug transport across the BBB are thoroughly examined. By integrating multi-omic studies and the application of artificial intelligence, future directions aim to unravel the complex TJ regulatory network for precision medicine approaches in CNS disorders. Overall, this literature review, which integrates current evidence and novel data from reputable databases, highlights the crucial roles of TJs concerning CNS health and disease. It is expected to promote further investigation of TJ physiology as a basis for innovative diagnostics and therapies to enhance neurological care.