Copper-mediated amyloid-β toxicity is associated with an intermolecular histidine bridge

Abstract

Amyloid-β peptide (Aβ) is pivotal to the pathogenesis of Alzheimer disease. Here we report the formation of a toxic Aβ-Cu 2+ complex formed via a histidine-bridged dimer, as observed at Cu 2+/ peptide ratios of >0.6:1 by EPR spectroscopy. The toxicity of the Aβ-Cu 2+ complex to cultured primary cortical neurons was attenuated when either the π- or τ-nitrogen of the imidazole side chains of His were methylated, thereby inhibiting formation of the His bridge. Toxicity did not correlate with the ability to form amyloid or perturb the acyl-chain region of a lipid membrane as measured by diphenyl-1,3,5-hexatriene anisotropy, but did correlate with lipid peroxidation and dityrosine formation. 31P ..