Tight junction proteins of the blood–brain barrier (BBB TJs)

Tight junction proteins of the blood–brain barrier (BBB) are a specialized complex of transmembrane and scaffold proteins that seal the paracellular space between brain capillary endothelial cells. The primary components include claudins (specifically claudin-5), occludin, and junctional adhesion molecules (JAMs), which are linked to the cytoskeleton via zonula occludens (ZO) proteins (1, 2). These proteins are essential for maintaining the high electrical resistance and selective permeability of the BBB, protecting the central nervous system from toxins and pathogens while regulating nutrient transport (3). Dysregulation or breakdown of these proteins is a hallmark of several neurological disorders, including multiple sclerosis, stroke, and Alzheimer's disease, where it contributes to neuroinflammation and edema (4). In drug development, these proteins are targeted to either stabilize the barrier in disease states or transiently open it to facilitate the delivery of large-molecule therapeutics to the brain (5). However, therapeutic manipulation of tight junctions poses risks such as uncontrolled entry of plasma proteins and potential neurotoxicity (6). Citations: (1) Stamatovic, S. M., et al. (2016). Essays in Biochemistry; (2) Greene, C., et al. (2019). Genes & Development; (3) Daneman, R., & Prat, A. (2015). Cold Spring Harbor Perspectives in Biology; (4) Keaney, J., & Campbell, M. (2015). Therapeutic Delivery; (5) Luissint, A. C., et al. (2012). Fluids and Barriers of the CNS; (6) Abbott, N. J., et al. (2010). Neurobiology of Disease.

Other names

Zonula occludensOccludinClaudinsJunctional adhesion moleculesJAMsBlood-brain barrier tight junctions

Transient disruption of paracellular seals to enhance drug delivery or stabilization of junctional complexes to restore barrier integrity.