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J Biol Chem. 2017 Jan 27;292(4):1404-1413. doi: 10.1074/jbc.M116.762526. Epub 2016 Dec 7.

Ion Channel Formation by Amyloid-β42 Oligomers but Not Amyloid-β40 in Cellular Membranes.

Author information

1
From the School of Biological and Chemical Sciences, Queen Mary, University of London, Mile End Road, London E1 4NS, United Kingdom and.
2
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.
3
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.

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.

KEYWORDS:

Alzheimer's disease; Aβ; amyloid-β; ion channel; membrane; oligomer; pore; toxicity

PMID:
27927987
PMCID:
PMC5270483
DOI:
10.1074/jbc.M116.762526
[Indexed for MEDLINE]
Free PMC Article

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