Amyloid- Peptide A-3pE-42 Induces Lipid Peroxidation, Membrane Permeabilization, and Calcium Influx in Neurons

Pyroglutamate-modified amyloid- (pΕ-Aβ) is a highly neurotoxic amyloid-β (Aβ) isoform and is enriched in the brains of individuals with Alzheimer disease compared with healthy aged controls. Pyroglutamate formation increases the rate ofAβ oligomerization and alters the interactions of Aβ with Cu²⁺ and lipids; however, a link between these properties and the toxicity of pE-Aβ peptides has not been established.Wereport here that Aβ3pE-42 has an enhanced capacity to cause lipid peroxidation in primary cortical mouse neurons compared with the fulllength isoform (Aβ(1-42)). In contrast, Aβ(1-42) caused a significant elevation in cytosolic reactive oxygen species, whereas Aβ3pE-42 did not.Wealso report that Aβ3pE-42 preferentially associates with neuronal membranes and triggers Ca2²⁺ influx that can be partially blocked by theN-methyl-D-aspartate receptor antagonist MK-801. Aβ3pE-42 further caused a loss of plasma membrane integrity and remained bound to neurons at significantly higher levels thanAβ(1-42) over extended incubations. Pyroglutamate formation was additionally found to increase the relative efficiency of Aβ-dityrosine oligomer formation mediated by copper-redox cycling.