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.
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