Methylation of the imidazole side chains of the Alzheimer disease amyloid-β peptide results in abolition of superoxide dismutase-like structures and inhibition of neurotoxicity

Abstract

The toxicity of the amyloid-β peptide (Aβ) is thought to be responsible for the neurodegeneration associated with Alzheimer disease. Generation of hydrogen peroxide has been implicated as a key step in the toxic pathway. Aβ coordinates the redox active metal ion Cu2+ to catalytically generate H2O2. Structural studies on the interaction of Aβ with Cu have suggested that the coordination sphere about the Cu2+ resembles the active site of superoxide dismutase 1. To investigate the potential role for such structures in the toxicity of Aβ, two novel Aβ40 peptides, Aβ40(HisτMe) and Aβ40(HisτMe), have been prepared, in which the histidine residues 6, 13, and 14 have been substituted with modified h..