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

A central hallmark of Alzheimer's disease is the presence of extracellular amyloid plaques chiefly consisting of amyloid-beta (A beta) peptides in the brain interstitium. A beta largely exists in two isoforms, 40 and 42 amino acids long, but a large body of evidence points toA beta (1-42) rather than A beta (1-40) as the cytotoxic form. One proposed mechanism by which A beta 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 A beta (1-40) and A beta (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 A beta (1-40) and A beta (1-42). A beta preparations were characterized with transmission electron microscopy and thioflavin T fluorescence. A beta was then exposed to the extracellular face of excised membranes, and transmembrane currents were monitored using patch clamp. Our data indicated that A beta (1-42) assemblies in oligomeric preparations form voltage-independent, non-selective ion channels. In contrast, A beta (1-40) oligomers, fibers, and monomers did not form channels. Ion channel conductance results suggested that A beta (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 A beta (1-42) contains unique structural features that facilitate membrane insertion and channel formation, now aligning ion channel formation with the differential neurotoxic effect of A beta (1-40) and A beta (1-42) in Alzheimer's disease.