Npc1 deficiency impairs brain vascular integrity in mouse model of Niemann-Pick disease type C1

Niemann-Pick disease type C1 is a rare and fatal neurodegenerative disorder caused by mutations in the NPC1 gene. Proper formation and function of vascular system are essential for maintaining homeostasis of the central nervous system. However, the vascular contribution to NPC1 pathogenesis remains largely unexplored. Here, we demonstrate that loss of Npc1, a transmembrane protein involved in intracellular cholesterol trafficking, results in vascular abnormalities in the mouse brain. Npc1-deficient mice exhibit distorted vascular architecture, increased blood-brain barrier (BBB) permeability, and enhanced microglia-endothelial cell contacts. Investigation of molecular perturbations upon endothelial Npc1 deficiency shows impairment of lipid metabolism and compromised Rap1 signaling and tight junctions in endothelial cells. These changes were in part reverted by release of lysosomal cholesterol. Collectively, these results suggest that Npc1 is involved in the regulation of brain vascular integrity and highlight brain endothelial cells as a potential therapeutic target for NPC1 disease.