Amyloid-ß Peptide Aß3pE-42 Induces Lipid Peroxidation, Membrane Permeabilization, and Calcium Influx in Neurons.

ABSTRACT

Pyroglutamate-modified amyloid-ß (pE-Aß) is a highly neurotoxic amyloid-ß (Aß) isoform and is enriched in the brains of individuals with Alzheimer disease compared with healthy aged controls. Pyroglutamate formation increases the rate of Aß oligomerization and alters the interactions of Aß with Cu(2+) and lipids; however, a link between these properties and the toxicity of pE-Aß peptides has not been established. We report here that Aß3pE-42 has an enhanced capacity to cause lipid peroxidation in primary cortical mouse neurons compared with the full-length isoform (Aß(1-42)). In contrast, Aß(1-42) caused a significant elevation in cytosolic reactive oxygen species, whereas Aß3pE-42 did not. We also report that Aß3pE-42 preferentially associates with neuronal membranes and triggers Ca(2+) influx that can be partially blocked by the N-methyl-d-aspartate receptor antagonist MK-801. Aß3pE-42 further caused a loss of plasma membrane integrity and remained bound to neurons at significantly higher levels than Aß(1-42) over extended incubations. Pyroglutamate formation was additionally found to increase the relative efficiency of Aß-dityrosine oligomer formation mediated by copper-redox cycling.