Self-Assembly of Aβ1-42 into Globular Neurotoxins
2003
Amyloid β 1−42 (Aβ1-42) is a self-associating peptide that becomes neurotoxic upon aggregation. Toxicity originally was attributed to the presence of large, readily formed Aβ fibrils, but a variety of other toxic species are now known. The current study shows that Aβ1-42 can self-assemble into small, stable globular assemblies free of fibrils and protofibrils. Absence of large molecules was verified by atomic force microscopy (AFM) and nondenaturing gel electrophoresis. Denaturing electrophoresis revealed that the globular assemblies comprised oligomers ranging from trimers to 24mers. Oligomers prepared at 4 °C stayed fibril-free for days and remained so when shifted to 37 °C, although the spectrum of sizes shifted toward larger oligomers at the higher temperature. The soluble, globular Aβ1-42 oligomers were toxic to PC12 cells, impairing reduction of MTT and interfering with ERK and Rac signal transduction. Occasionally, oligomers were neither toxic nor recognized by toxicity-neutralizing antibodies, sug...
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