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Meprin β: A novel regulator of blood-brain barrier integrity
Markus Gindorf1, Steffen E Storck1, Anke Ohler1
1Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
Abstract:
The metalloprotease meprin β (Mep1b) is capable of cleaving cell-adhesion molecules in different tissues (e.g. skin, kidney and intestine) and is dysregulated in several diseases associated with barrier breakdown (Alzheimer´s disease, kidney disruption, inflammatory bowel disease). In this study, we demonstrate that Mep1b is a novel regulator of tight junction (TJ) composition and blood-brain barrier (BBB) integrity in brain endothelium. In Mep1b-transfected mouse brain endothelial cells (bEnd.3), we observed a reduction of the TJ protein claudin-5, decreased transendothelial electrical resistance (TEER) and an elevated permeability to paracellular diffusion marker [14C]-inulin. Analysis of global Mep1b knock-out (Mep1b-/-) mice showed increased TJ protein expression (claudin-5, occludin, ZO-1) in cerebral microvessels and increased TEER in cultivated primary mouse brain endothelial compared to wild-type (wt) mice. Furthermore, we investigated the IgG levels in cerebrospinal fluid (CSF) and the brain water content as additional permeability markers and detected lower IgG levels and reduced brain water content in Mep1b-/- mice compared to wt mice. Showing opposing features in overexpression and knock-out, we conclude that Mep1b plays a role in regulating brain endothelial TJ-proteins and therefore affecting BBB tightness in vitro and in vivo.
Insights
Meprin β (Mep1b) regulates blood-brain barrier (BBB) integrity by affecting tight junction proteins. Knocking out Mep1b strengthens the BBB, reducing permeability and brain water content.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Meprin β (Mep1b) is a metalloprotease involved in cleaving cell-adhesion molecules.
- Mep1b dysregulation is linked to diseases characterized by barrier breakdown, including Alzheimer's disease and inflammatory bowel disease.
Purpose of the Study:
- To investigate the role of Meprin β (Mep1b) in regulating tight junction (TJ) composition and blood-brain barrier (BBB) integrity in brain endothelium.
Main Methods:
- Meprin β (Mep1b) overexpression in mouse brain endothelial cells (bEnd.3).
- Analysis of global Mep1b knock-out (Mep1b-/-) mice and wild-type (wt) littermates.
- Measurement of transendothelial electrical resistance (TEER) and paracellular permeability using [14C]-inulin.
- Assessment of tight junction protein expression (claudin-5, occludin, ZO-1) in cerebral microvessels.
- Quantification of IgG levels in cerebrospinal fluid (CSF) and brain water content.
Main Results:
- Mep1b overexpression in bEnd.3 cells reduced claudin-5 expression, decreased TEER, and increased permeability.
- Mep1b-/- mice exhibited increased expression of TJ proteins (claudin-5, occludin, ZO-1) in cerebral microvessels.
- Primary brain endothelial cells from Mep1b-/- mice showed higher TEER compared to wt mice.
- Mep1b-/- mice had lower IgG levels in CSF and reduced brain water content compared to wt mice.
Conclusions:
- Meprin β (Mep1b) acts as a novel regulator of tight junction protein composition in brain endothelium.
- Mep1b influences blood-brain barrier (BBB) tightness both in vitro and in vivo.
- Targeting Mep1b may offer therapeutic strategies for conditions involving BBB dysfunction.
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