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Amyloid-β(1-42) aggregation initiates its cellular uptake and cytotoxicity

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Item Type:Article
Title:Amyloid-β(1-42) aggregation initiates its cellular uptake and cytotoxicity
Creators Name:Jin, S. and Kedia, N. and Illes-Toth, E. and Haralampiev, I. and Prisner, S. and Herrmann, A. and Wanker, E.E. and Bieschke, J.
Abstract:The accumulation of amyloid beta peptide(1-42) (Abeta(1-42)) in extracellular plaques is one of the pathological hallmarks of Alzheimer disease (AD). Several studies have suggested that cellular reuptake of Abeta(1-42) may be a crucial step in its cytotoxicity, but the uptake mechanism is not yet understood. Abeta may be present in an aggregated form prior to cellular uptake. Alternatively, monomeric peptide may enter the endocytic pathway and conditions in the endocytic compartments may induce the aggregation process. Our study aims to answer the question whether aggregate formation is a prerequisite or a consequence of Abeta endocytosis. We visualized aggregate formation of fluorescently labeled Abeta(1-42) and tracked its internalization by human neuroblastoma cells and neurons. beta-Sheet-rich Abeta(1-42) aggregates entered the cells at low nanomolar concentration of Abeta(1-42). In contrast, monomer uptake faced a concentration threshold and occurred only at concentrations and time scales that allowed Abeta(1-42) aggregates to form. By uncoupling membrane binding from internalization, we found that Abeta(1-42) monomers bound rapidly to the plasma membrane and formed aggregates there. These structures were subsequently taken up and accumulated in endocytic vesicles. This process correlated with metabolic inhibition. Our data therefore imply that the formation of beta-sheet-rich aggregates is a prerequisite for Abeta(1-42) uptake and cytotoxicity.
Keywords:Aggregation, Amyloid, Amyloid-{beta} (AB), Kinetics, Protein Folding, Internalization
Source:Journal of Biological Chemistry
ISSN:0021-9258
Publisher:American Society for Biochemistry and Molecular Biology (U.S.A.)
Volume:291
Number:37
Page Range:19590-19606
Date:9 September 2016
Official Publication:https://doi.org/10.1074/jbc.M115.691840
PubMed:View item in PubMed

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