A critical concentration of N-terminal pyroglutamylated amyloid beta drives the misfolding of Ab1-42 into more toxic aggregates

摘要

A wide consensus based on robust experimental evidence indicates pyroglutamylated amyloid-beta isoform (A beta pE3-42) as one of the most neurotoxic peptides involved in the onset of Alzheimer's disease. Furthermore, A beta pE3-42 co-oligomerized with excess of A beta 1-42, produces oligomers and aggregates that are structurally distinct and far more cytotoxic than those made from A beta 1-42 alone. Here, we investigate quantitatively the influence of A beta pE3-42 on biophysical properties and biological activity of A beta 1-42. We tested different ratios of A beta pE3-42/A beta 1-42 mixtures finding a correlation between the biological activity and the structural conformation and morphology of the analyzed mixtures. We find that a mixture containing 5% A beta pE3-42, induces the highest disruption of intracellular calcium homeostasis and the highest neuronal toxicity. These data correlate to an high content of relaxed antiparallel beta-sheet structure and the coexistence of a population of big spheroidal aggregates together with short fibrils. Our experiments provide also evidence that A beta pE3-42 causes template-induced misfolding of A beta 1-42 at ratios below 33%. This means that there exists a critical concentration required to have seeding on A beta 1-42 aggregation, above this threshold, the seed effect is not possible anymore and A beta pE3-42 controls the total aggregation kinetics. (C) 2016 Elsevier Ltd. All rights reserved.