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(HisπMe), have been prepared, in which the histidine residues 6, 13, and 14 have been substituted with modified histidines where either the π- or τ-nitrogen of the imidazole side chain is methylated to prevent the formation of bridging histidine moieties. These modifications did not inhibit the ability of these peptides to form fibrils. However, the modified peptides were four times more effective at generating H2O2 than the native sequence. Despite the ability to generate more H2O2, these peptides were not neurotoxic. Whereas the modifications to the peptide altered the metal binding properties, they also inhibited the interaction between the peptides and cell surface membranes. This is consistent with the notion that Aβ-membrane interactions are important for neurotoxicity and that inhibiting these interactions has therapeutic potential.