Cellular distribution of ferric iron, ferritin, transferrin and divalent metal transporter 1 (DMT1) in substantia nigra and basal ganglia of normal and beta 2-microglobulin deficient mouse brain

We examined whether high levels of circulatory iron may cause iron accumula tion in the brain. In particular, we focussed on the substantia nigra and b asal ganglia as several papers have indicated that iron may accumulate here and cause death of dopaminergic neurons. Normal mice and a mouse model of hereditary haemochromatosis, the beta 2-microglobulin (beta 2m) knock out [ beta 2m (-/-)] mouse, which has high levels of circulating iron due to incr eased iron absorption, were examined. The iron concentration in livers were : 170 +/- 15 mu g/g (mean +/- SD) in controls and 1010 +/- 50 mu g/g in bet a 2m (-/-) mice (p<0.001), whereas in the brain the respective values were 47 +/- 1 mu g/g and 53 +/- 2 mu g/g (p<0.02). Hence, the difference between cerebral iron levels of normal and beta 2m (-/-) mice was small. Histologi cal examination of the brains revealed an unequivocal distribution of ferri c iron, ferritin, transferrin and divalent metal transporter 1 (DMT1), whic h were indistinguishable when normal and beta 2m (-/-) mice were compared. In the substantia nigra and basal ganglia, ferric iron and the iron-binding proteins were present in identical cell types, which mainly comprised olig odendrocytes and microglia. Neurons were lightly labelled with transferrin and DMT1. The virtual lack of an increase in cerebral iron in beta 2m (-/-) mice clearly shows that the blood-brain barrier (BBB) is capable of restri cting the transport of excess plasma iron into the brain.