Alzheimer's disease amyloid-beta binds copper and zinc to generate an allosterically ordered membrane-penetrating structure containing superoxide dismutase-like subunits

Amyloid beta peptide (A beta) is the major constituent of extracellular pla ques and perivascular amyloid deposits, the pathognomonic neuropathological lesions of Alzheimer's disease. Gu(2+) and Zn2+ bind A beta, inducing aggr egation and giving rise to reactive oxygen species. These reactions may pla y a deleterious role in the disease state, because high concentrations of i ron, copper, and zinc have been located in amyloid in diseased brains. Here we show that coordination of metal ions to A beta is the same in both aque ous solution and lipid environments, with His(6), His(13), and His(14) all involved. At Cu2+/peptide molar ratios >0.3, A beta coordinated a second Cu 2+ atom in a highly cooperative manner. This effect was abolished if the hi stidine residues were methylated at. N-epsilon2, indicating the presence of bridging histidine residues, as found in the active site of superoxide dis mutase, Addition of Cu2+ Or Zn2+ to A beta in a negatively charged lipid en vironment caused a conformational change from beta -sheet to alpha -helix, accompanied by peptide oligomerization and membrane penetration, These resu lts suggest that metal binding to A beta generated an allosterically ordere d membrane-penetrating oligomer linked by superoxide dismutase-like bridgin g histidine residues.