Iron activates Alzheimer's amyloid precursor protein synthesis through an iron responsive element (IRE) mRNA binding...

Amyloid precursor protein (APP) contributes significantly to neuronal degeneration and is linked to the etiology of Alzheimer's disease (AD). Iron increases synthesis rates of the Alzheimer's APP through an iron responsive element (IRE) RNA stem loop in their 5'-untranslated regions (5'-UTRs). Docking results revealed the binding of APP IRE with eIF4F with appreciable binding affinity, making several close interactions involving hydrogen bonding. Fluorescence based binding revealed APP IRE binds specifically to eIF4F with a nanomolar affinity. Iron (labile as Fe²⁺) further increased APP IRE binding to eIF4F, which outcompetes with IRP1 binding. Thermodynamic parameters of APP IRE∙eIF4F interactions were elucidated further by utilizing temperature dependence binding affinity data. It was quite evident from the thermodynamic calculations that APP IRE spontaneously binds to eIF4F with a postulated existence of hydrogen bonding. Fe²⁺ increased the enthalpic (ΔH) and free energy (ΔG) contribution to the APP IRE∙eIF4F complex formation, resulting in a more stable complex formation through increasing hydrogen bonding. This suggests that iron plays specific role on thermodynamics of these RNA-protein interactions. Exogenous eIF4F restored iron-dependent APP mRNA translation in vitro in eIF4F-depleted extracts. Fe²⁺ increases APP mRNA translation. Whereas IRP1 inhibits APP expression. Furthermore, addition of Fe²⁺ reversed IRP1 inhibition of protein synthesis by reducing inhibitor protein (IRP1) binding and increasing activator protein (eIF4F) binding. These results provide insight into APP mRNA translation control through translation initiation factors binding and uncover role of iron in the regulatory process.