Objective: To create a mechanistic computational model of iron transport between the circulation and brain, permitting in silico investigation of homeostatic regulation of iron at the human blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCB).

Background: The human brain utilizes iron in numerous essential processes. Iron trafficking is tightly regulated to minimize damage from iron-mediated excess free radical generation. Iron uptake across the BBB utilizes the iron transport protein transferrin, and is dependent on transferrin receptor expression (TfR) at the BBB (C. Morris, Brain 2011 v134 p924). Disruption of brain iron homeostasis is evident in certain neurodegenerative disorders, and elevated iron in the dopaminergic neurons of the substantia nigra (SN) is a particular feature of Parkinson’s disease (PD). Dysregulation of iron in PD is not fully understood. Treatment with oral chelators that appear to modify iron levels in the SN can delay progression of early-stage PD (D. Devos et. al., Antioxid. Redox Signal. 2014 v21 p195). A computational model that describes brain iron homeostasis at a level that replicates experimental observations, and predicts the impact of perturbations (e.g. with chelating drugs) is highly desirable.

Methods: A mechanistic, multi-compartment in silico model of brain iron trafficking has been created using COPASI: Biochemical System Simulator software. The model comprises nonlinear ordinary differential equations to characterize the kinetics of each chemical species incorporated. Experimentally determined model parameter values for compartmental volumes, and initial concentrations and rate constants for each species, were derived from the literature.

Results: Model simulations accurately replicate the kinetics of iron uptake across the BBB with independently determined experimental data. In response to simulated iron overload in the blood circulation the model predicts that regulatory activity at the BBB/BCB, utilizing intracellular-scale control circuits, protects against excessive iron loading in the brain.

Conclusions: This new model provides an in silico resource to explore the impact of iron dysregulation and iron modifying drugs on the primary compartments of the human brain, and to better understand mechanisms of action of existing therapeutics.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-computational-model-of-iron-transport-between-the-blood-circulation-and-the-brain/