FIGURE 1.

(A) Different functions of soluble and membrane-bound ceruloplasmin. Ferroxidase activity of membrane-bound CP is essential since only Fe³⁺ (but not Fe²⁺) can be incorporated into plasma transferrin, and then delivered to other cells (mainly erythroid precursors) via Transferrin Receptor 1 (TfR1). (B,C) Model of iron cross-talk between astrocytes and neuronal cells. (B) Ceruloplasmin is needed to oxidize Fe²⁺ into Fe³⁺, the only iron form that can be bound to transferrin for appropriate iron uptake by neurons through the transferrin receptor type 1 (TfR1). (C) Lack of ceruloplasmin leads to initial iron accumulation into astrocytes and starvation of neurons, with ensuing alteration of energetic metabolism and synthesis of neurotransmitters. This later stimulates the neuronal uptake alternative sources of iron, like non-transferrin-bound iron (NTBI), which is further toxic.