Key roles of Arg(5), Tyr(10) and his residues in Aß-heme peroxidase: relevance to Alzheimer's disease.

ABSTRACT

Recent reports show that heme binds to amyloid ß-peptide (Aß) in the brain of Alzheimer's disease (AD) patients and forms Aß-heme complexes, thus leading a pathological feature of AD. However, the important biological relevance to AD etiology, resulting from human Aß-heme peroxidase formation, was not well characterized. In this study, we used wild-type and mutated human Aß1-16 peptides and investigated their Aß-heme peroxidase activities. Our results indicated that both histidine residues (His(13), His(14)) in Aß1-16 and free histidine enhanced the peroxidase activity of heme, hence His residues were essential in peroxidase activity of Aß-heme complexes. Moreover, Arg(5) was found to be the key residue in making the Aß1-16-heme complex as a peroxidase. Under oxidative and nitrative stress conditions, the Aß1-16-heme complexes caused oxidation and nitration of the Aß Tyr(10) residue through promoting peroxidase-like reactions. Therefore, these residues (Arg(5), Tyr(10) and His) were pivotal in human Aß-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 Aß-heme complex lacks peroxidase activity and it does not show AD, implicating the novel significance of these residues as well as human Aß-heme peroxidase in the pathology of AD.