Distribution of transferrin and ferritin binding in normal and multiple sclerotic human brains.

Abstract

Delivery of iron to the brain traditionally has been considered the responsibility of transferrin. However, transferrin receptors in brain are located primarily within gray matter areas rather than in the iron rich white matter tracts. In this report we present the first demonstration of ferritin binding sites in human brain and provide evidence that these binding sites are primarily in white matter tracts. This distribution of ferritin binding is opposite of that seen for the distribution of the transferrin receptor in normal adult human brain. Ferritin binds to human brain tissue in a competitive and saturable manner with a dissociation constant of 0.35 nM and a binding site density of 116.7 fmol/mg protein. In brain tissue from multiple sclerotic (MS) patients the normal pattern of transferrin and ferritin binding distributions is disrupted. Ferritin binding is absent in the lesion itself and in the immediate periplaque region within the white matter but returns to normal as the distance from the lesion becomes greater. In direct contrast to ferritin binding, transferrin binding in the MS tissue is present in the white matter tracts, but only in the periplaque region. The periplaque region also contains transferrin receptor positive cells (as determined by immunocytochemistry) morphologically consistent with oligodendrocytes. Gray matter binding of transferrin in MS patients appears normal. These data provide the initial evidence of ferritin binding in human brain, address the enigma of the apparent absence of an iron delivery system to the iron-rich white matter, and suggest loss of ferritin binding is involved in or is a consequence of demyelination associated with MS.