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Amyloid β peptide (Aβ) is the major constituent of extracellular plaques and perivascular amyloid deposits, the pathognomonic neuropathological lesions of Alzheimer's disease. Cu²⁺ and Zn²⁺ bind Aβ, inducing aggregation and giving rise to reactive oxygen species. These reactions may play a deleterious role in the disease state, because high concentrations of iron, copper, and zinc have been located in amyloid in diseased brains. Here we show that coordination of metal ions to Aβ is the same in both aqueous solution and lipid environments, with His⁶, His¹³, and His¹⁴ all involved. At Cu²⁺/peptide molar ratios >0.3, Aβ coordinated a second Cu²⁺ atom in a highly cooperative manner. This effect was abolished if the histidine residues were methylated at N^ε2, indicating the presence of bridging histidine residues, as found in the active site of superoxide dismutase. Addition of Cu²⁺ or Zn²⁺ to Aβ in a negatively …