title: Amyloid-β Peptide Aβ3pE-42 Induces Lipid Peroxidation, Membrane Permeabilization, and Calcium Influx in Neurons.
abstract: Pyroglutamate-modified amyloid-β (pE-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 of Aβ oligomerization and alters the interactions of Aβ with Cu(2+) and lipids; however, a link between these properties and the toxicity of pE-Aβ peptides has not been established. We report here that Aβ3pE-42 has an enhanced capacity to cause lipid peroxidation in primary cortical mouse neurons compared with the full-length isoform (Aβ(1-42)). In contrast, Aβ(1-42) caused a significant elevation in cytosolic reactive oxygen species, whereas Aβ3pE-42 did not. We also report that Aβ3pE-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. Aβ3pE-42 further caused a loss of plasma membrane integrity and remained bound to neurons at significantly higher levels than Aβ(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.
authors.affiliation: From the Florey Institute of Neuroscience and Mental Health.
authors.forename: Adam P
authors.identifier: http://orcid.org/0000-0002-8181-4975
authors.initials: AP
authors.lastname: Gunn
authors.affiliation: From the Florey Institute of Neuroscience and Mental Health.
authors.forename: Bruce X
authors.identifier: http://orcid.org/0000-0002-1687-4138
authors.initials: BX
authors.lastname: Wong
authors.affiliation: Departments of Pathology and.
authors.forename: Timothy
authors.identifier: http://orcid.org/0000-0001-6757-586X
authors.initials: T
authors.lastname: Johanssen
authors.affiliation: Materials Characterisation and Fabrication Platform, University of Melbourne, Parkville, Melbourne 3010, Australia and.
authors.forename: James C
authors.identifier: http://orcid.org/0000-0002-4911-4223
authors.initials: JC
authors.lastname: Griffith
authors.affiliation: From the Florey Institute of Neuroscience and Mental Health.
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.affiliation: From the Florey Institute of Neuroscience and Mental Health, Departments of Pathology and.
authors.forename: Ashley I
authors.identifier: http://orcid.org/0000-0001-8259-9069
authors.initials: AI
authors.lastname: Bush
authors.affiliation: From the Florey Institute of Neuroscience and Mental Health, Pharmacology and Therapeutics, and.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Barnham
authors.affiliation: From the Florey Institute of Neuroscience and Mental Health, Departments of Pathology and the School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, West Yorkshire LS2 9JT, United Kingdom.
authors.forename: James A
authors.initials: JA
authors.lastname: Duce
authors.affiliation: From the Florey Institute of Neuroscience and Mental Health, rcherny@unimelb.edu.au.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cherny
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001205:Ascorbic Acid / Q000737:chemistry; D020013:Calcium Signaling; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D003300:Copper / Q000737:chemistry; D006801:Humans; D015227:Lipid Peroxidation; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D066329:Protein Aggregates; D011761:Pyrrolidonecarboxylic Acid / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D066329:Protein Aggregates; D017382:Reactive Oxygen Species; C532271:amyloid beta-protein (3-42), pyroglutamyl(3)-; D014443:Tyrosine; D003300:Copper; C007543:dityrosine; D001205:Ascorbic Acid; D011761:Pyrrolidonecarboxylic Acid
keywords: Alzheimer disease; amyloid-beta (Aβ); dityrosine; lipid peroxidation; oligomer; pyroglutamate; reactive oxygen species (ROS)