科研之友
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摘要
The accumulation of amyloid peptide(1-42) (A(1-42)) in extracellular plaques is one of the pathological hallmarks of Alzheimer disease (AD). Several studies have suggested that cellular reuptake of A(1-42) may be a crucial step in its cytotoxicity, but the uptake mechanism is not yet understood. A 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 A endocytosis. We visualized aggregate formation of fluorescently labeled A(1-42) and tracked its internalization by human neuroblastoma cells and neurons. -Sheet-rich A(1-42) aggregates entered the cells at low nanomolar concentration of A(1-42). In contrast, monomer uptake faced a concentration threshold and occurred only at concentrations and time scales that allowed A(1-42) aggregates to form. By uncoupling membrane binding from internalization, we found that A(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 -sheet-rich aggregates is a prerequisite for A(1-42) uptake and cytotoxicity.
- 出版日期2016-9-9
