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

Research output: Contribution to journalArticlepeer-review

Abstract

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 languageEnglish
Article numbere63253
JournaleLife
Volume10
DOIs
StatePublished - 1 Dec 2021

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