CLDN5

CLDN5 (claudin-5) encodes a major tight junction protein that is highly enriched in brain endothelial cells and functions as a critical determinant of blood-brain barrier (BBB) integrity by restricting paracellular permeability.[1][2] Mechanistically, CLDN5 forms endothelial tight junction complexes that regulate size-selective molecular transport, and genetic deletion of Cldn5 increases BBB permeability to molecules smaller than approximately 800 Da while preserving overall vascular morphology.[3][4] Therefore, CLDN5 is considered a central regulator of BBB homeostasis and selective barrier function in the central nervous system.[1][3] In disease models, reduced CLDN5 expression is associated with BBB disruption and has been linked to neurological, neuroinflammatory, neurodegenerative, and psychiatric disorders, including epilepsy, multiple sclerosis, Alzheimer's disease, depression, and schizophrenia.[2][5] Mechanistically, ischemia-reperfusion injury decreases claudin-5 expression and redistributes tight junction components in parallel with BBB leakage, supporting a role for CLDN5 in vascular barrier dysfunction during neurological injury.[6] Compared with related claudin isoforms, CLDN5 is the dominant tightening claudin at the BBB, whereas CLDN1 and CLDN3 are expressed at substantially lower levels and CLDN12 alone does not reproduce the restrictive barrier properties mediated by CLDN5.[4][7] For experimental applications, transient modulation of CLDN5 has attracted interest as a strategy to enhance brain drug delivery, while restoration of CLDN5 expression is being investigated to improve BBB integrity in CNS disorders.[1][2]