The amyloid precursor protein (APP) is a membrane-spanning glycoprotein that is the source of beta A4 peptides, which aggregate in Alzheimer's disease to form senile plaques. APP is cleaved within the beta A4 sequence to release a soluble N-terminal derivative (APPsol), which has a wide range of trophic and protective functions. In the current study we have examined the hypothesis that iron availability may modulate expression or processing of APP, whose mRNA contains, based on sequence homology, a putative iron response element (IRE). Radiolabeled APP and its catabolites were precipitated from lysates and conditioned medium of stably transfected HEK 293 cells using antibodies selective for C-terminal, beta A4, and N-terminal domains. The relative abundance of the different APP catabolites under different conditions of iron availability was determined by quantitative densitometry after separation by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The data show a specific effect on the production of APPsol. Using standard conditions previously established for IRE studies, it was found that iron chelation reduces APPsol production, whereas iron level elevation augments it. No changes were observed in levels of immature and mature APP holoprotein or in the C-terminal alpha-secretase derivative C83, beta A4, and p3 peptides. The specificity for modulatory changes in APPsol suggests that iron acts at the level of alpha-secretase activity. In addition to its modulatory effects, iron at very high levels was found to inhibit maturation of APP and production of its downstream catabolites without blocking formation of immature APP. The data establish a potential physiological role for iron in controlling the processing of APP.(ABSTRACT TRUNCATED AT 250 WORDS)