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

Amyloid-beta peptide (A beta) is pivotal to the pathogenesis of Alzheimer disease. Here we report the formation of a toxic A beta-Cu2+ complex formed via a histidine-bridged dimer, as observed at Cu2+/ peptide ratios of > 0.6:1 by EPR spectroscopy. The toxicity of the A beta-Cu2+ complex to cultured primary cortical neurons was attenuated when either the pi- or tau-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. P-31 magic angle spinning solid-state NMR showed that A beta and A beta-Cu2+ complexes interacted at the surface of a lipid membrane. These findings indicate that the generation of the A beta toxic species is modulated by the Cu2+ concentration and the ability to form an intermolecular His bridge.

Introduction: Casting new light on old stones

The purpose of this monograph is to take a new look at various aspects of stone artefact analysis that reveal important and exciting new information about the past. This invovles reorienting our methodological approach to stone artefacts as well as the questions asked of them. The papers making up this volume tackle a number of issues that have long been at the heart of archaeology’s problematic relationship with stone artefacts, including our understanding of the dynamic nature of past stoneworking practices, the utility of traditional classificatory schemes, and ways to unlock the vast amount of information about the strategic role of lithic technology that resides in stone artefact assemblages.