Jin, S;
Kedia, N;
Illes-Toth, E;
Haralampiev, I;
Prisner, S;
Herrmann, A;
Wanker, EE;
(2016)
Amyloid-β(1-42) Aggregation Initiates Its Cellular Uptake and Cytotoxicity.
Journal of Biological Chemistry
, 291
(37)
pp. 19590-19606.
10.1074/jbc.M115.691840.
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Abstract
The accumulation of amyloid β peptide(1-42) (Aβ(1-42)) in extracellular plaques is one of the pathological hallmarks of Alzheimer disease (AD). Several studies have suggested that cellular reuptake of Aβ(1-42) may be a crucial step in its cytotoxicity, but the uptake mechanism is not yet understood. Aβ 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 Aβ endocytosis. We visualized aggregate formation of fluorescently labeled Aβ(1-42) and tracked its internalization by human neuroblastoma cells and neurons. β-Sheet-rich Aβ(1-42) aggregates entered the cells at low nanomolar concentration of Aβ(1-42). In contrast, monomer uptake faced a concentration threshold and occurred only at concentrations and time scales that allowed Aβ(1-42) aggregates to form. By uncoupling membrane binding from internalization, we found that Aβ(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 β-sheet-rich aggregates is a prerequisite for Aβ(1-42) uptake and cytotoxicity.
| Type: | Article |
|---|---|
| Title: | Amyloid-β(1-42) Aggregation Initiates Its Cellular Uptake and Cytotoxicity |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1074/jbc.M115.691840 |
| Publisher version: | http://dx.doi.org/10.1074/jbc.M115.691840 |
| Language: | English |
| Additional information: | This version is the version of record. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | aggregation, amyloid, amyloid-β (AB), internalization, kinetics, protein folding, Alzheimer Disease, Amyloid beta-Peptides, Cell Line, Cell Membrane, Endocytosis, Humans, Peptide Fragments, Protein Aggregation, Pathological, Protein Structure, Secondary, Protein Transport |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases > MRC Prion Unit at UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10059287 |
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