Targeting Pdzrn3 maintains adult blood-brain barrier and central nervous system homeostasis. Issue 4 (April 2022)

• Record Type: Journal Article
• Authors: Gueniot, Florian; Rubin, Sebastien; Bougaran, Pauline; Abelanet, Alice; Morel, Jean Luc; Bontempi, Bruno; Proust, Carole; Dufourcq, Pascale; Couffinhal, Thierry; Duplàa, Cecile
• Is Part Of: Journal of cerebral blood flow & metabolism. Volume 42:Issue 4(2022)
• Page Start: 613
• Page End: 629
• Publication Date: 2022-04
• Subjects: Vascular cognitive impairment -- blood brain barrier -- vascular permeability -- Wnt pathway -- endothelial tight junction; Cerebral circulation -- Periodicals; Brain -- Metabolism -- Periodicals; Brain -- Blood-vessels -- Periodicals; Cerebrovascular disease -- Periodicals; 612.824
• DOI: 10.1177/0271678X211048981
• Languages: English
• ISSNs: 0271-678X

Abstract

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.