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

By C. Curtain, F. Ali, I. Volitakis, R. Cherny, R. Norton, K. Beyreuther, C. Barrow, Colin L. Masters, Ashley I. Bush, K. Barnham. Journal of Biological Chemistry, 2001

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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 Nε 2, 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.

Subfields: Nutrition and Dietetics, Pharmacology, Physiology

View Paper: https://www.semanticscholar.org/paper/78243050a5dda4ec7e71ed54324db627fce54039

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Citations in the corpus

Evidence that amyloid beta-peptide-induced lipid peroxidation and its sequelae in Alzheimer's disease brain contribute to neuronal death. (2002, background): “These findings, which support the hypothesis of A -induced lipid peroxidation, are consistent with low-angle X-ray studies on A [25–35] [61]or NMR studies on A (1–42)[21], showing that the peptide is soluble in lipid bilayers with such orientation that the methionine-35 residue is deeply inserted in”
Neurodegenerative diseases and oxidative stress (2004, methodology): “The interactions of synthetic Aβ with copper, zinc and iron have been probed using nuclear magnetic resonance and electron paramagnetic resonance spectroscop”
Oxidative Stress in Neurodegenerative Diseases: From Molecular Mechanisms to Clinical Applications (2017, background): “Therefore, the supplementation of Cu and Zn has been suggested as a novel strategy to decrease Aβ-induced ROS generation and metalcatalyzed Aβ deposition [56].”
Amyloid β-peptide (1-42)-induced Oxidative Stress and Neurotoxicity: Implications for Neurodegeneration in Alzheimer's Disease Brain. A Review (2002, background): “ing and physical studies of Ab suggest that Met is indeed located in the lipid bilayer of neurons.[ 46 ] If”