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bioRxiv · 10.1101/2021.08.12.456150

Nano-scale Architecture of Blood-Brain Barrier Tight-Junctions

Sasson, E.·Anzi, S.·Bell, B.·Yakovian, O.·Zorsky, M.·Deutsch, U.·Engelhardt, B.·Sherman, E.·Vatine, G. D.·Dzikowski, R.·Ben-Zvi, A.
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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. Developmentally, 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.

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Sasson, E., Anzi, S., Bell, B., Yakovian, O., Zorsky, M., Deutsch, U., Engelhardt, B., Sherman, E., Vatine, G. D., Dzikowski, R., Ben-Zvi, A.. 2021-08-13. Nano-scale Architecture of Blood-Brain Barrier Tight-Junctions. https://doi.org/10.1101/2021.08.12.456150

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