Abstract
Amyloid beta peptide (Abeta) is the major constituent of extracellular plaques and perivascular amyloid deposits, the pathognomonic neuropathological lesions of Alzheimer's disease. Cu(2+) and Zn(2+) bind Abeta, 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 Abeta is the same in both aqueous solution and lipid environments, with His(6), His(13), and His(14) all involved. At Cu(2+)/peptide molar ratios >0.3, Abeta coordinated a second Cu(2+) atom in a highly cooperative manner. This effect was abolished if the histidine residues were methylated at N(epsilon)2, indicating the presence of bridging histidine residues, as found in the active site of superoxide dismutase. Addition of Cu(2+) or Zn(2+) to Abeta in a negatively charged lipid environment caused a conformational change from beta-sheet to alpha-helix, accompanied by peptide oligomerization and membrane penetration. These results suggest that metal binding to Abeta generated an allosterically ordered membrane-penetrating oligomer linked by superoxide dismutase-like bridging histidine residues.
Highlights
The amyloid  peptide (A)1 is a normally soluble 4.3-kDa peptide found in all biological fluids, but it accumulates as the major constituent of the extracellular deposits that are the pathologic hallmarks of Alzheimer’s disease (AD) [1]
This hypothesis is supported by the recent observation that senile plaques and neurofibrillary tangles isolated from AD brains were capable of generating reactive oxygen species and that copper and iron were essential [17]
This peptide was prepared by incorporating histidine residues that were already methylated at the N⑀2 nitrogens of the imidazole ring into the synthesis of A28, and its identity was verified by mass spectrometry and NMR
Summary
The amyloid  peptide (A) is a normally soluble 4.3-kDa peptide found in all biological fluids, but it accumulates as the major constituent of the extracellular deposits that are the pathologic hallmarks of Alzheimer’s disease (AD) [1]. Because elevated levels of copper (400 M), zinc (1 mM), and iron (1 mM) are found in amyloid deposits in AD-affected brains [15, 16], the oxidative stress observed in AD may be related to the production of reactive oxygen species by metal-bound forms of A. This hypothesis is supported by the recent observation that senile plaques and neurofibrillary tangles isolated from AD brains were capable of generating reactive oxygen species and that copper and iron were essential [17]. The aim of the present study was to characterize the structural consequences of A binding to Cu2ϩ and Zn2ϩ in solution and to identify amino acid residues involved in metal binding
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