The history of iron in the brain.

Brain iron research began in the late nineteenth century when Zaleski (1886) made a quantitative analysis of one human brain and correlated iron levels with observations on stained slices and some microscopic sections. Gradually, the realization grew that the central nervous system (CNS) contained iron which was different from hemoglobin-iron. This non-heme iron was found in highest concentrations in globus pallidus, substantia nigra, red nucleus, and dentate nucleus. The enhancement of the traditional histochemical stain, potassium ferrocyanide in hydrochloric acid, by incubating the reacted sections in a solution of diaminobenzidine and hydrogen peroxide, revealed iron in many cell types of the CNS, including neurons, microglia, oligodendroglia, and some astrocytes. A large proportion of the soluble brain iron was shown to be present in ferritin. Brain ferritin was found to be very similar to the protein from other organs in that it contained heavy and light subunits. Several investigators reported the presence of other iron-related proteins in the central nervous system, including transferrin, transferrin receptor, and the ferritin repressor protein. Brain was shown to respond to the extravasation of blood by converting the iron in heme to hemosiderin by a sequence of steps which was quite similar to the process in extracerebral organs. The methods of molecular biology have contributed greatly to our understanding of brain iron but many questions remain about its unique anatomical distribution and its role in degenerative diseases such as Parkinson's disease and Alzheimer's dementia.