Impairment of the BBB in cluadin-5 knock-out mice (right).

On page 653, Nitta et al. show that removal of the tight junction component claudin-5 makes the murine blood–brain barrier (BBB) selectively permeable to small molecules. Although considerably more work is needed before this approach can be applied clinically, the finding could be a boon for drug delivery to the central nervous system.

Although it was first described over a century ago, it has been shown more recently that the BBB consists of intercellular tight junctions, which prevent most molecules in the bloodstream from reaching the brain. In the new work, the authors found that the tight junctions of the BBB are primarily composed of the membrane proteins claudin-5 and claudin-12. Mice with a homozygous deletion in the claudin-5 gene appear to develop normally, and do not show signs of bleeding or edema, but do exhibit a striking abnormality in tracer experiments. Although the BBB of the knockout animals still blocks large molecules, it permits molecules smaller than ∼800 D to pass into the central nervous system.

Unfortunately, all of the claudin-5 knockout mice died within ten hours of birth for unknown reasons. The authors are now trying to generate conditional deletions to characterize the functions of claudin-5 and claudin-12 in more detail. ▪