Amyloid precursor protein (APP) is a transmembrane glycoprotein widely expressed in mammalian tissues and plays a central role in Alzheimer's disease. However, its physiological function remains elusive. Cu2+ binding and reduction activities have been described in the extracellular APP135-156 region, which might be relevant for cellular copper uptake and homeostasis. Here, we assessed Cu2+ reduction and Cu-64 uptake in two human HEK293 cell lines overexpressing APP. Our results indicate that Cu2+ reduction increased and cells accumulated larger levels of copper, maintaining cell viability at supra-physiological levels of Cu2+ ions. Moreover, wild-type cells exposed to both Cu2+ ions and APP135-155 synthetic peptides increased copper reduction and uptake. Complementation of function studies in human APP751 transformed Fre1 defective Saccharomyces cerevisiae cells rescued low Cu2+ reductase activity and increased Cu-64 uptake. We conclude that Cu2+ reduction activity of APP facilitates copper uptake and may represent an early step in cellular copper homeostasis. (C) 2009 Elsevier Inc. All rights reserved.