Figure 7. Model for the role of APP in cellular iron export and its inhibition in Alzheimer's disease.

Fpn transports Fe²⁺ from the cytosol across the plasma membrane. Fe²⁺ is then converted to Fe³⁺ by a membrane-bound or soluble ferroxidase such as Cp or APP (shown). The absence of the ferroxidase results in decreased iron release into the extracellular space, as Fe²⁺ is unable to be converted into Fe³⁺. APP ferroxidase is inhibited by extracellular Zn²⁺ (Figures 2A & 6B), which can exchange from Aβ:Zn²⁺ aggregates (Figure 6D). Free Zn²⁺ is normally buffered by the presence of ligands such as metallothioneins (including metallothionein III in the extracellular space), which are lost in AD (Uchida et al., 1991). Loss of metallothioneins and other Zn²⁺ buffers may lie upstream in amyloid pathology, APP ferroxidase inhibition and neuronal iron accumulation in AD. See also Figure S6.