Abstract
At the blood–brain barrier (BBB), claudin (Cldn)-5 is thought to be the dominant tight junction (TJ) protein, with minor contributions from Cldn3 and -12, and occludin. However, the BBB appears ultrastructurally normal in Cldn5 knock-out mice, suggesting that further Cldns and/or TJ-associated marvel proteins (TAMPs) are involved. Microdissected human and murine brain capillaries, quickly frozen to recapitulate the in vivo situation, showed high transcript expression of Cldn5, -11, -12, and -25, and occludin, but also abundant levels of Cldn1 and -27 in man. Protein levels were quantified by a novel epitope dilution assay and confirmed the respective mRNA data. In contrast to the in vivo situation, Cldn5 dominates BBB expression in vitro, since all other TJ proteins are at comparably low levels or are not expressed. Cldn11 was highly abundant in vivo and contributed to paracellular tightness by homophilic oligomerization, but almost disappeared in vitro. Cldn25, also found at high levels, neither tightened the paracellular barrier nor interconnected opposing cells, but contributed to proper TJ strand morphology. Pathological conditions (in vivo ischemia and in vitro hypoxia) down-regulated Cldn1, -3, and -12, and occludin in cerebral capillaries, which was paralleled by up-regulation of Cldn5 after middle cerebral artery occlusion in rats. Cldn1 expression increased after Cldn5 knock-down. In conclusion, this complete Cldn/TAMP profile demonstrates the presence of up to a dozen TJ proteins in brain capillaries. Mouse and human share a similar and complex TJ profile in vivo, but this complexity is widely lost under in vitro conditions.
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Abbreviations
- BBB:
-
Blood–brain barrier
- BSA:
-
Bovine serum albumin
- CFP:
-
Cyan fluorescent protein
- Cldn:
-
Claudin
- CRFR:
-
Corticotrophin-releasing factor receptor
- DMEM:
-
Dulbecco’s modified Eagle’s medium
- EDTA:
-
Ethylenediaminetetraacetic acid
- FCS:
-
Fetal calf serum
- FRET:
-
Fluorescence resonance energy transfer
- HB-EGF:
-
Heparin-binding epidermal growth factor-like growth factor
- HEK:
-
Human embryonic kidney
- MBP:
-
Maltose-binding protein
- MCAO:
-
Middle cerebral artery occlusion
- MDCK:
-
Madin–Darby canine kidney cells
- MRI:
-
Magnetic resonance imaging
- Ocln:
-
Occludin
- PBS:
-
Phosphate buffered saline
- PEI:
-
Polyethylenimine
- qRT-PCR:
-
Quantitative real-time polymerase chain reaction
- RCA1:
-
Ricinus communis agglutinin
- SDS-PAGE:
-
Sodium dodecyl sulfate polyacryl gel electrophoresis
- TAMP:
-
Tight junction-associated Marvel protein
- TER:
-
Transcellular electrical resistance
- TJ:
-
Tight junction
- TX-100:
-
Triton X-100
- VEGF:
-
Vascular endothelial growth factor
- YFP:
-
Yellow fluorescent protein
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Acknowledgements
The authors wish to thank Michael Krauss (FMP Berlin) for help in lentiviral preparation, Susanne Müller (Charité Universitätsmedizin Berlin, Dept. Experimental Neurology) for help in MRI experiments and Ria Knittel (University Hospital, Tübingen, Dept. Pathology and Neuropathology) for skillful assistance with the freeze-fracture technology.
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Berndt, P., Winkler, L., Cording, J. et al. Tight junction proteins at the blood–brain barrier: far more than claudin-5. Cell. Mol. Life Sci. 76, 1987–2002 (2019). https://doi.org/10.1007/s00018-019-03030-7
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DOI: https://doi.org/10.1007/s00018-019-03030-7