Alzheimer's Disease Amyloid-β Binds Copper and Zinc to Generate an Allosterically Ordered Membrane-penetrating Structure Containing Superoxide Dismutase-like Subunits

Abstract

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 Nε2, 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 charged lipid environment caused a conformational change from β-sheet to α-helix, accompanied by peptide oligomerization and membrane penetration. These results suggest that metal binding to Aβ generated an allosterically ordered membrane-penetrating oligomer linked by superoxide dismutase-like bridging histidine residues.