Imbalance of iron influx and efflux causes brain iron accumulation over time in the healthy adult rat

Brain iron accumulation is supposed to play a central role in neurodegeneration by inducing oxidative stress. Currently it is unknown to which extent iron entering brain over lifetime exchanges with body iron or if uptake of iron is unidirectional without significant efflux from brain. To study brain iron dynamics in vivo, up to three stable isotope tracers were fed continuously with a standard rodent diet up to 5 months to healthy adult male Wistar rats (n = 8) in a staggered design. Brain iron uptake was found to be bi-directional but iron influx and efflux were unbalanced leading inevitably to brain iron accumulation over time. Brain iron turnover was found to be very low at a half-life of ca. 9 months for tracer iron entering brain. Observed tracer accumulation in brain iron can be extrapolated to an increase of brain iron by ca. 30% in the healthy rats from early adulthood to the end of their lives. In contrast to current beliefs that brain uptake of dietary iron is negligible during adulthood following short-term radiotracer studies, our long-term feeding experiments point to a possible role of the diet in brain iron accumulation and, subsequently, neurodegeneration.