Nano-scale architecture of blood-brain barrier tight-junctions
Summary
Tight junctions (TJs) between blood-brain barrier (BBB) endothelial cells construct a robust physical barrier, whose damage underlies BBB dysfunctions related to several neurodegenerative diseases. What makes these highly specialized BBB-TJs extremely restrictive remains unknown. Here, we use super-resolution microscopy (dSTORM) to uncover new structural and functional properties of BBB TJs. Focusing on three major components, Nano-scale resolution revealed sparse (occludin) vs. clustered (ZO1/claudin-5) molecular architecture. In mouse development, permeable TJs become first restrictive to large molecules, and only later to small molecules, with claudin-5 proteins arrangement compacting during this maturation process. Mechanistically, we reveal that ZO1 clustering is independent of claudin-5 in vivo. In contrast to accepted knowledge, we found that in the developmental context, total levels of claudin-5 inversely correlate with TJ functionality. Our super-resolution studies provide a unique perspective of BBB TJs and open new directions for understanding TJ functionality in biological barriers, ultimately enabling restoration in disease or modulation for drug delivery. © 2021, Sasson et al.
| Authors | Sasson E, Anzi S, Bell B, Yakovian O, Zorsky M, Deutsch U, Engelhardt B, Sherman E, Vatine G, Dzikowski R, Ben-Zvi A |
|---|---|
| Journal | eLife |
| Publication Date | 2021 Dec 24;10 |
| PubMed | 34951586 |
| PubMed Central | PMC8747500 |
| DOI | 10.7554/elife.63253 |