title: Ion Channel Formation by Amyloid-β42 Oligomers but Not Amyloid-β40 in Cellular Membranes.
abstract: A central hallmark of Alzheimer's disease is the presence of extracellular amyloid plaques chiefly consisting of amyloid-β (Aβ) peptides in the brain interstitium. Aβ largely exists in two isoforms, 40 and 42 amino acids long, but a large body of evidence points to Aβ(1-42) rather than Aβ(1-40) as the cytotoxic form. One proposed mechanism by which Aβ exerts toxicity is the formation of ion channel pores that disrupt intracellular Ca2+homeostasis. However, previous studies using membrane mimetics have not identified any notable difference in the channel forming properties between Aβ(1-40) and Aβ(1-42). Here, we tested whether a more physiological environment, membranes excised from HEK293 cells of neuronal origin, would reveal differences in the relative channel forming ability of monomeric, oligomeric, and fibrillar forms of both Aβ(1-40) and Aβ(1-42). Aβ preparations were characterized with transmission electron microscopy and thioflavin T fluorescence. Aβ was then exposed to the extracellular face of excised membranes, and transmembrane currents were monitored using patch clamp. Our data indicated that Aβ(1-42) assemblies in oligomeric preparations form voltage-independent, non-selective ion channels. In contrast, Aβ(1-40) oligomers, fibers, and monomers did not form channels. Ion channel conductance results suggested that Aβ(1-42) oligomers, but not monomers and fibers, formed three distinct pore structures with 1.7-, 2.1-, and 2.4-nm pore diameters. Our findings demonstrate that only Aβ(1-42) contains unique structural features that facilitate membrane insertion and channel formation, now aligning ion channel formation with the differential neurotoxic effect of Aβ(1-40) and Aβ(1-42) in Alzheimer's disease.
authors.affiliation: From the School of Biological and Chemical Sciences, Queen Mary, University of London, Mile End Road, London E1 4NS, United Kingdom and.
authors.forename: David C
authors.initials: DC
authors.lastname: Bode
authors.affiliation: the Blizard Institute, Centre for Neuroscience and Trauma, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, 4 Newark Street, London E1 2AT, United Kingdom m.d.baker@qmul.ac.uk.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Baker
authors.affiliation: From the School of Biological and Chemical Sciences, Queen Mary, University of London, Mile End Road, London E1 4NS, United Kingdom and j.viles@qmul.ac.uk.
authors.forename: John H
authors.initials: JH
authors.lastname: Viles
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)
keywords: Alzheimer's disease; Aβ; amyloid-β; ion channel; membrane; oligomer; pore; toxicity