Characterisation of brain iron accumulation in mouse models of systemic iron overload — ASN Events
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Characterisation of brain iron accumulation in mouse models of systemic iron overload (#351)

Dan Johnstone 1 2 , Moones Heidari 1 , Bulent Acikyol 1 , Ross Graham 3 4 , Mike House 5 , Anita Chura 3 , Roheeth Delima 3 , John Olynyk 3 6 , Debbie Trinder 3 , Liz Milward 1
  1. School of Biomedical Sciences, University of Newcastle, Newcastle, Australia
  2. Bosch Institute and Discipline of Physiology, University of Sydney, Sydney, Australia
  3. School of Medicine and Pharmacology, University Of Western Australia , , Australia
  4. School of Biomedical Sciences, Curtin University of Technology, , WA, Australia
  5. Department of Physics, University Of Western Australia , , Australia
  6. Department of Gastroenterology, Fremantle Hospital, , WA, Australia

Disruption of brain iron homeostasis can cause fatal neurodegenerative disease, however debate surrounds whether the brain is affected in more common disorders of systemic iron overload such as hereditary haemochromatosis, which is usually caused by mutations in the HFE gene or occasionally the transferrin receptor 2 (TFR2) gene.

We utilised four different mouse models (age 10 weeks, n=4-8 males/group) to explore the effects of iron overload disorders on the brain; wildtype AKR mice fed an iron-supplemented diet (2% carbonyl iron, 3 weeks), mice with disruption of either the Hfe gene (Hfe-/-) or Tfr2 gene (Tfr2mut) and mice with simultaneous disruption of both genes (Hfe-/-xTfr2mut). Brain iron was assessed by inductively coupled plasma-atomic emission spectroscopy (ICP-AES), non-haem iron assay and Perls staining.

Relative to control mice, dietary iron-supplemented, Hfe-/- and Tfr2mut mice all showed comparable increases (~3-fold) in liver iron concentration but no detectable change in total brain iron levels. In contrast, the recently developed Hfe-/-xTfr2mut model, which more accurately reproduces features of human haemochromatosis such as liver fibrosis, showed significantly higher brain levels of total iron (by ICP-AES) and non-haem iron (>1.4-fold increase, p<0.025) than control mice. Histological analyses revealed extreme iron accumulation in the choroid plexus and more modest loading in various other brain structures (e.g. red nuclei). Western immunoblotting detected increased levels of the iron storage protein ferritin (2.3-fold increase, p=0.0005), while microarray and qRT-PCR detected decreased transcripts for the cellular iron uptake molecule transferrin receptor 1 (2-fold decrease, p=0.0005), consistent with increased intracellular iron.

To our knowledge, Hfe-/-xTfr2mut mice are the first model of genetic hemochromatosis to exhibit detectable brain iron accumulation, providing a new model for studying the effects of brain iron accumulation on brain pathology and function. Further studies are required to determine the nature of any pathological or functional effects, as well as the reasons underlying the striking localisation of excess iron to the choroid plexus.