Regulatory mechanisms for iron transport across the blood-brain barrier.

Abstract Many critical metabolic functions in the brain require adequate and timely delivery of iron. However, most studies when considering brain ironuptake have ignored the ironrequirements of the endothelial cells that form the blood-brain barrier (BBB). Moreover, current models of BBB irontransport do not address regional regulation of brain ironuptake or how neurons, when adapting to metabolic demands, can acquire more iron. In this study, we demonstrate that both iron-poor transferrin (apo-Tf) and the iron chelator, deferoxamine, stimulate release of ironfrom iron-loaded endothelial cells in an in vitro BBB model. The role of the endosomaldivalent metal transporter 1 ( DMT1) in BBB ironacquisition and transport has been questioned. Here, we show that inhibition of DMT1alters the transport of ironand Tf across the endothelial cells. These data support an endosome-mediated model of Tf-bound ironuptake into the brain and identifies mechanisms for local regional regulation of brain ironuptake. Moreover, our data provide an explanation for the disparity in the ratio of Tf to irontransport into the brain that has confounded the field.