Cellular and Molecular Life Sciences

, Volume 76, Issue 10, pp 1987–2002 | Cite as

Tight junction proteins at the blood–brain barrier: far more than claudin-5

  • Philipp Berndt
  • Lars WinklerEmail author
  • Jimmi Cording
  • Olga Breitkreuz-Korff
  • André Rex
  • Sophie Dithmer
  • Valentina Rausch
  • Rosel Blasig
  • Matthias Richter
  • Anje Sporbert
  • Hartwig Wolburg
  • Ingolf E. Blasig
  • Reiner F. HaseloffEmail author
Original Article


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.


Brain endothelium Ischemia Protein–protein interaction Laser capture microdissection Neurovasculature 



Blood–brain barrier


Bovine serum albumin


Cyan fluorescent protein




Corticotrophin-releasing factor receptor


Dulbecco’s modified Eagle’s medium


Ethylenediaminetetraacetic acid


Fetal calf serum


Fluorescence resonance energy transfer


Heparin-binding epidermal growth factor-like growth factor


Human embryonic kidney


Maltose-binding protein


Middle cerebral artery occlusion


Madin–Darby canine kidney cells


Magnetic resonance imaging




Phosphate buffered saline




Quantitative real-time polymerase chain reaction


Ricinus communis agglutinin


Sodium dodecyl sulfate polyacryl gel electrophoresis


Tight junction-associated Marvel protein


Transcellular electrical resistance


Tight junction


Triton X-100


Vascular endothelial growth factor


Yellow fluorescent protein



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.

Supplementary material

18_2019_3030_MOESM1_ESM.pdf (641 kb)
Supplementary material 1 (PDF 641 kb)


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Philipp Berndt
    • 1
  • Lars Winkler
    • 1
    Email author
  • Jimmi Cording
    • 1
  • Olga Breitkreuz-Korff
    • 1
  • André Rex
    • 2
  • Sophie Dithmer
    • 1
  • Valentina Rausch
    • 1
  • Rosel Blasig
    • 1
  • Matthias Richter
    • 3
  • Anje Sporbert
    • 3
  • Hartwig Wolburg
    • 4
  • Ingolf E. Blasig
    • 1
  • Reiner F. Haseloff
    • 1
    Email author
  1. 1.Leibniz-Forschungsinstitut für Molekulare PharmakologieBerlinGermany
  2. 2.Department of Experimental NeurologyCharité-Universitätsmedizin BerlinBerlinGermany
  3. 3.Max-Delbrück-Centrum für Molekulare MedizinBerlinGermany
  4. 4.Institut für Pathologie und NeuropathologieUniversität TübingenTübingenGermany

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