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

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.

Upregulation of Dickkopf1 by oscillatory shear stress accelerates atherogenesis.

UNLABELLED: Numerous clinical studies have highlighted the pivotal role Dickkopf (DKK) 1 plays in atherosclerosis, but the underlying mechanisms remain unknown. The present study was designed to explore the contribution of DKK1 to the development of atherosclerosis under oscillatory shear stress. Oscillatory shear stress applied to endothelial cells induced DKK1 expression, which peaked at 6 h. siRNA knockdown or silencing DKK1 by lentiviral gene delivery counteracted the increased monocyte adhesion and impaired endothelial tight junction induced by oscillatory shear stress, thereby attenuating atherogenesis in ApoE-/- mice. As well, activation of endothelial proteinase-activated receptor 1 (PAR1) and its downstream transcription factor, cAMP response element-binding protein (CREB), was critical to the increased expression of DKK1 under oscillatory shear stress. We provide evidence that DKK1 contributes to the development of atherosclerosis under conditions of oscillatory shear stress. A better understanding of the role played by DKK1 in atherogenesis may provide clinicians with opportunities to prevent atherosclerosis. KEY MESSAGE: Disturbed oscillatory flow increases DKK1 expression. DKK1 knockdown attenuates OSS-induced monocyte adhesion and endothelial impairment. Genetic silencing of DKK1 limits atherogenesis in ApoE-/- mice. Activation of the PAR1/CREB pathway contributes to the upregulation of DKK1 via OSS. DKK1 is a promising candidate with respect to the treatment of atherosclerosis.