Transferrin is required for normal distribution of ⁵⁹Fe and ⁵⁴Mn in mouse brain

Hypotransferrinemia (hpx/hpx) is a genetic defect in mice resulting in <1% of normal plasma transferrin (Tf) concentrations; heterozygotes for this mutation (+/hpx) have low circulating Tf concentrations. These mice provide a unique opportunity to examine the role of Tf in Fe and Mn transport in the brain. Twenty weanling wild-type BALB/cJ mice, 15 +/hpx mice, and 12 hpx/hpx mice of both sexes were injected i.v. with either ⁵⁴MnCl₂ or ⁵⁹FeCl₃ either 1 h or 1 week before killing at 12 weeks of age. Total brain counts of ⁵⁴Mn and ⁵⁹Fe were measured, and regional brain distributions were assessed by autoradiography. Hypotransferrinemia did not affect total brain Mn uptake. However, 1 week after i.v. injection, hpx/hpx mice had less ⁵⁴Mn in forebrain structures including cerebral cortex, corpus callosum, striatum, and substantia nigra. The +/hpx mice had the highest total brain ⁵⁹Fe accumulation 1 h after i.v. injection. A striking effect of regional distribution of ⁵⁹Fe was noted 1 week after injection; in hpx/hpx mice, ⁵⁹Fe was located primarily in choroid plexus, whereas in +/+ and +/hpx mice ⁵⁹Fe was widely distributed, with relatively high amounts in cerebral cortex and cerebellum. We interpret these data to mean that Tf is necessary for the transport of Fe but not Mn across the blood-brain barrier, and that there is a Tf-independent uptake mechanism for iron in the choroid plexus. Additionally, these data suggest that endogenous synthesis of Tf is necessary for Fe transport from the choroid plexus.