Recent reports show that heme binds to amyloid beta-peptide (A beta) in the brain of Alzheimer's disease (AD) patients and forms A beta-heme complexes, thus leading a pathological feature of AD. However, the important biological relevance to AD etiology, resulting from human A beta-heme peroxidase formation, was not well characterized. In this study, we used wild-type and mutated human A beta(1-16) peptides and investigated their A beta-heme peroxidase activities. Our results indicated that both histidine residues (His(13), His(14)) in A beta(1-16) and free histidine enhanced the peroxidase activity of heme, hence His residues were essential in peroxidase activity of A beta-heme complexes. Moreover, Arg(5) was found to be the key residue in making the A beta(1-16)-heme complex as a peroxidase. Under oxidative and nitrative stress conditions, the A beta(1-16)-heme complexes caused oxidation and nitration of the A beta Tyr(10) residue through promoting peroxidase-like reactions. Therefore, these residues (Arg(5), Tyr(10) and His) were pivotal in human A beta-heme peroxidase activity. However, three of these residues (Arg(5,) Tyr(10)and His(13)) identified in this study are all absent in rodents, where rodent A beta-heme complex lacks peroxidase activity and it does not show AD, implicating the novel significance of these residues as well as human A beta-heme peroxidase in the pathology of AD. (C) 2014 Elsevier Inc. All rights reserved.