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

• DOI: 10.1074/jbc.m116.762526
• Publication Date: 2016-12-08T01:15:13Z
• Authors: David C. Bode; Mark D. Baker; John H. Viles
• Keywords: Thioflavin; Amyloid (mycology); Oligomer

A central hallmark of Alzheimer's disease is the presence extracellular amyloid plaques chiefly consisting amyloid-β (Aβ) peptides in brain interstitium. Aβ largely exists two isoforms, 40 and 42 amino acids long, but a large body evidence points to Aβ(1-42) rather than Aβ(1-40) as cytotoxic form. One proposed mechanism by which exerts toxicity formation ion channel pores that disrupt intracellular Ca2+ homeostasis. However, previous studies using membrane mimetics have not identified any notable difference forming properties between Aβ(1-42). Here, we tested whether more physiological environment, membranes excised from HEK293 cells neuronal origin, would reveal differences relative ability monomeric, oligomeric, fibrillar forms both preparations were characterized with transmission electron microscopy thioflavin T fluorescence. was then exposed face membranes, transmembrane currents monitored patch clamp. Our data indicated assemblies oligomeric form voltage-independent, non-selective channels. In contrast, oligomers, fibers, monomers did Ion conductance results suggested formed three distinct pore structures 1.7-, 2.1-, 2.4-nm diameters. findings demonstrate only contains unique structural features facilitate insertion formation, now aligning differential neurotoxic effect disease.