Amyloid- Peptide A3pE-42 Induces Lipid Peroxidation, Membrane Permeabilization, and Calcium Influx in Neurons

Pyroglutamate-modified amyloid- (pE-A) is a highly neurotoxic amyloid- (A) isoform and is enriched in the brains of individuals with Alzheimer disease compared with healthy aged controls. Pyroglutamate formation increases the rate of A oligomerization and alters the interactions of A with Cu2+ and lipids; however, a link between these properties and the toxicity of pE-A peptides has not been established. We report here that A3pE-42 has an enhanced capacity to cause lipid peroxidation in primary cortical mouse neurons compared with the full-length isoform (A(1-42)). In contrast, A(1-42) caused a significant elevation in cytosolic reactive oxygen species, whereas A3pE-42 did not. We also report that A3pE-42 preferentially associates with neuronal membranes and triggers Ca2+ influx that can be partially blocked by the N-methyl-d-aspartate receptor antagonist MK-801. A3pE-42 further caused a loss of plasma membrane integrity and remained bound to neurons at significantly higher levels than A(1-42) over extended incubations. Pyroglutamate formation was additionally found to increase the relative efficiency of A-dityrosine oligomer formation mediated by copper-redox cycling.