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

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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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  1. Philipp Berndt and Lars Winkler contributed equally.

Authors and Affiliations

  1. Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Robert-Rössle-Str. 10, 13125, Berlin, Germany

    Philipp Berndt, Lars Winkler, Jimmi Cording, Olga Breitkreuz-Korff, Sophie Dithmer, Valentina Rausch, Rosel Blasig, Ingolf E. Blasig & Reiner F. Haseloff

  2. Department of Experimental Neurology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany

    André Rex

  3. Max-Delbrück-Centrum für Molekulare Medizin, Robert-Rössle-Str. 10, 13125, Berlin, Germany

    Matthias Richter & Anje Sporbert

  4. Institut für Pathologie und Neuropathologie, Universität Tübingen, Liebermeisterstraße 8, 72076, Tübingen, Germany

    Hartwig Wolburg

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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

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