Nano-scale architecture of blood-brain barrier tight-junctions

Esther Sasson, Shira Anzi, Batia Bell, Oren Yakovian, Meshi Zorsky, Urban Deutsch, Britta Engelhardt, Eilon Sherman, Gad D. Vatine, Ron Dzikowski, Ayal Ben-Zvi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


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.

Original languageAmerican English
Article numbere63253
StatePublished - 24 Dec 2021

Bibliographical note

Funding Information:
We would like to thank; Mss. Sivan Gelb, Kian Atamny and Victoria Miller of the Ben-Zvi group for scientific and writing inputs, Drs. Avihu Klar and Danny Ben-Zvi for scientific inputs, Dr. Gillian Kay for valuable scientific editing, Dr. Norman Grover for his helpful advice regarding statistical analyses, and Ms. Yaara Arad for help with data presentation. We wish to dedicate this work to the memory of Prof. Morris J. Karnovsky of Harvard Medical School, a scientific giant and pioneer of the BBB research field. We are grateful for his mentorship and scientific support, and especially for encouraging us to pursue our endeavor of super resolution imaging of BBB TJs.

Publisher Copyright:
© 2021, eLife Sciences Publications Ltd. All rights reserved.


  • blood-brain-barrier
  • tight-junction
  • super-resolution
  • endothelium
  • Mouse


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