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

J Cereb Blood Flow Metab. 2022 Apr;42(4):613-629. doi: 10.1177/0271678X211048981. Epub 2021 Oct 13.

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.

Keywords: Vascular cognitive impairment; Wnt pathway; blood brain barrier; endothelial tight junction; vascular permeability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease* / metabolism
  • Animals
  • Biological Transport
  • Blood-Brain Barrier* / metabolism
  • Capillary Permeability
  • Endothelial Cells / metabolism
  • Homeostasis
  • Mice
  • Ubiquitin-Protein Ligases* / genetics
  • Ubiquitin-Protein Ligases* / metabolism

Substances

  • PDZRN3 protein, mouse
  • Ubiquitin-Protein Ligases