Targeting Pdzrn3 maintains adult blood-brain barrier and central nervous system homeostasis

2021 ◽  
pp. 0271678X2110489
Author(s):  
Florian Gueniot ◽  
Sebastien Rubin ◽  
Pauline Bougaran ◽  
Alice Abelanet ◽  
Jean Luc Morel ◽  
...  
Keyword(s):  
Cognitive Decline ◽  
Blood Brain Barrier ◽  
Ubiquitin Ligase ◽  
Wnt Pathway ◽  
Target Gene ◽  
E3 Ubiquitin Ligase ◽  
Brain Barrier ◽  
Limited Data ◽  
Blood Brain ◽  
Gene Alterations

Blood brain barrier (BBB) disruption is a critical component of the pathophysiology of cognitive impairment of vascular etiology (VCI) and associated with Alzheimer’s disease (AD). The Wnt pathway plays a crucial role in BBB maintenance, but there is limited data on its role in cognitive pathologies. The E3 ubiquitin ligase PDZRN3 is a regulator of the Wnt pathway. In a murine model of VCI, overexpressing Pdzrn3 in endothelial cell (EC) exacerbated BBB hyperpermeability and accelerated cognitive decline. We extended these observations, in both VCI and AD models, showing that EC-specific depletion of Pdzrn3, reinforced the BBB, with a decrease in vascular permeability and a subsequent spare in cognitive decline. We found that in cerebral vessels, Pdzrn3 depletion protects against AD-induced Wnt target gene alterations and enhances endothelial tight junctional proteins. Our results provide evidence that Wnt signaling could be a molecular link regulating BBB integrity and cognitive decline under VCI and AD pathologies.

scholarly journals APOE4 leads to blood–brain barrier dysfunction predicting cognitive decline

Nature ◽  
2020 ◽  
Vol 581 (7806) ◽  
pp. 71-76 ◽  
Author(s):  
Axel Montagne ◽  
Daniel A. Nation ◽  
Abhay P. Sagare ◽  
Giuseppe Barisano ◽  
Melanie D. Sweeney ◽  
...  
Keyword(s):  
Cognitive Decline ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Barrier Dysfunction ◽  
Blood Brain

Blood-brain barrier breakdown, neuroinflammation, and cognitive decline in older adults

2018 ◽  
Vol 14 (12) ◽  
pp. 1640-1650 ◽  
Author(s):  
Gene L. Bowman ◽  
Loïc Dayon ◽  
Richard Kirkland ◽  
Jérôme Wojcik ◽  
Gwendoline Peyratout ◽  
...  
Keyword(s):  
Older Adults ◽  
Cognitive Decline ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Blood Brain ◽  
Barrier Breakdown ◽  
Blood Brain Barrier Breakdown

scholarly journals The Cross-Talk between Canonical and Non-Canonical Wnt-Dependent Pathways Regulates P-Glycoprotein Expression in Human Blood–Brain Barrier Cells

2014 ◽  
Vol 34 (8) ◽  
pp. 1258-1269 ◽  
Author(s):  
Martha L Pinzón-Daza ◽  
Iris C Salaroglio ◽  
Joanna Kopecka ◽  
Ruth Garzòn ◽  
Pierre-Olivier Couraud ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Cross Talk ◽  
Wnt Pathway ◽  
Glycogen Synthase ◽  
Tyrosine Phosphatase ◽  
Brain Barrier ◽  
Canonical Wnt Pathway ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Canonical Wnt

In this work, we investigate if and how transducers of the ‘canonical’ Wnt pathway, i.e., Wnt/glycogen synthase kinase 3 (GSK3)/β-catenin, and transducers of the ‘non-canonical’ Wnt pathway, i.e., Wnt/RhoA/RhoA kinase (RhoAK), cooperate to control the expression of P-glycoprotein (Pgp) in blood–brain barrier (BBB) cells. By analyzing human primary brain microvascular endothelial cells constitutively activated for RhoA, silenced for RhoA or treated with the RhoAK inhibitor Y27632, we found that RhoAK phosphorylated and activated the protein tyrosine phosphatase 1B (PTP1B), which dephosphorylated tyrosine 216 of GSK3, decreasing the GSK3-mediated inhibition of β-catenin. By contrast, the inhibition of RhoA/RhoAK axis prevented the activation of PTP1B, enhanced the GSK3-induced phosphorylation and ubiquitination of β-catenin, and reduced the β-catenin-driven transcription of Pgp. The RhoAK inhibition increased the delivery of Pgp substrates like doxorubicin across the BBB and improved the doxorubicin efficacy against glioblastoma cells co-cultured under a BBB monolayer. Our data demonstrate that in human BBB cells the expression of Pgp is controlled by a cross-talk between canonical and non-canonical Wnt pathways. The disruption of this cross-talk, e.g., by inhibiting RhoAK, downregulates Pgp and increases the delivery of Pgp substrates across the BBB.

scholarly journals Sex-Related Differences in Regional Blood–Brain Barrier Integrity in Non-Demented Elderly Subjects

2021 ◽  
Vol 22 (6) ◽  
pp. 2860
Author(s):  
Yeonsil Moon ◽  
Changmok Lim ◽  
Yeahoon Kim ◽  
Won-Jin Moon
Keyword(s):  
Sex Differences ◽  
Cognitive Decline ◽  
Blood Brain Barrier ◽  
Occipital Cortex ◽  
Brain Barrier ◽  
Elderly Subjects ◽  
Permeability Model ◽  
Assessment Scores ◽  
Blood Brain ◽  
Group Sex

The role of the blood–brain barrier (BBB) breakdown has been recognized as being important in Alzheimer’s disease pathogenesis. We aimed to evaluate whether regional BBB integrity differed according to sex and whether differences in BBB integrity changed as a consequence of aging or cognitive decline, using dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI). In total, 75 participants with normal cognition (NC) or mild cognitive impairment (MCI) underwent cognitive assessments and MRI examination including DCE-MRI. Regional Ktrans was calculated in cortical regions and the Patlak permeability model was used to calculate BBB permeability (Ktrans, min−1). Females had a lower median Ktrans in the cingulate and occipital cortices. In the “older old” group, sex differences in Ktrans were only observed in the occipital cortex. In the MCI group, sex differences in Ktrans were only observed in the occipital cortex. Age was the only predictor of cognitive assessment scores in the male MCI group; however, educational years and Ktrans in the occipital cortex could predict cognitive scores in the female MCI group. Our study revealed that females may have better BBB integrity in cingulate and occipital cortices. We also found that sex-related differences in BBB integrity are attenuated with aging or cognitive decline.

Sign in / Sign up

Export Citation Format

Share Document