Regulation of brain iron uptake by apo- and holo-transferrin is dependent on sex and delivery protein

Background: The brain requires iron for a number of processes, including energy production. Inadequate or excessive amounts of iron can be detrimental and lead to a number of neurological disorders. As such, regulation of brain iron uptake is required for proper functioning. Understanding both the movement of iron into the brain and how this process is regulated is crucial to both address dysfunctions with brain iron uptake in disease and successfully use the transferrin receptor uptake system for drug delivery. Methods: Using in vivo steady state infusions of apo- and holo-transferrin into the lateral ventricle, we demonstrate the regulatory effects of brain apo- and holo-transferrin ratios on the delivery of radioactive 55 Fe bound to transferrin or H-ferritin in male and female mice. In discovering sex differences in the response to apo and holo Tf infusions, ovariectomies were performed on female mice to interrogate the influence of circulating estrogen on regulation of iron uptake. Results: Our model reveals that both sex and type of iron delivery protein have significant effects on the regulation of iron uptake into the microvasculature and subsequent release into the brain. Furthermore, we show that cells of the microvasculature act as significant reservoirs of iron and release the iron in response to cues from the interstitial fluid of the brain. Conclusions: These findings extend our previous work to demonstrate that the regulation of brain iron uptake is influenced by both the mode in which iron is delivered and sex. These findings further emphasize the role of the microvasculature in regulating brain iron uptake and the importance of cues regarding iron status in the extracellular fluid.