Open AccessTargetingPdzrn3maintains adult blood-brain barrier and central nervous system homeostasis
Author(s) -
Florian Gueniot,
Sébastien Rubin,
Pauline Bougaran,
Alice Abélanet,
Jean-Luc Morel,
Bruno Bontempi,
Carole Proust,
Pascale Dufourcq,
Thierry Couffinhal,
Cécile Duplàa
Publication year - 2021
Publication title -
journal of cerebral blood flow and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.167
H-Index - 193
eISSN - 1559-7016
pISSN - 0271-678X
DOI - 10.1177/0271678x211048981
Subject(s) - wnt signaling pathway , blood–brain barrier , cognitive decline , neuroscience , central nervous system , biology , ubiquitin ligase , regulator , microbiology and biotechnology , dementia , medicine , disease , pathology , signal transduction , ubiquitin , gene , biochemistry
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.