期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2009
卷号：106
期号：48
页码：20324-20329
DOI：10.1073/pnas.0911281106
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：One of the neuropathological hallmarks of Alzheimer's disease (AD) is the amyloid plaque, primarily composed of aggregated amyloid-beta (A{beta}) peptide. In vitro, A{beta}1-42, the major alloform of A{beta} found in plaques, self-assembles into fibrils at micromolar concentrations and acidic pH. Such conditions do not exist in the extracellular fluid of the brain where the pH is neutral and A{beta} concentrations are in the nanomolar range. Here, we show that extracellular soluble A{beta} (sA{beta}) at concentrations as low as 1 nM was taken up by murine cortical neurons and neuroblastoma (SHSY5Y) cells but not by human embryonic kidney (HEK293) cells. Following uptake, A{beta} accumulated in Lysotracker-positive acidic vesicles (likely late endosomes or lysosomes) where effective concentrations (>2.5 {micro}M) were greater than two orders of magnitude higher than that in the extracellular fluid (25 nM), as quantified by fluorescence intensity using laser scanning confocal microscopy. Furthermore, SHSY5Y cells incubated with 1 {micro}M A{beta}1-42 for several days demonstrated a time-dependent increase in intracellular high molecular weight (HMW) (>200 kDa) aggregates, which were absent in cells grown in the presence of A{beta}1-40. Homogenates from these A{beta}1-42-loaded cells were capable of seeding amyloid fibril growth. These results demonstrate that A{beta} can be taken up by certain cells at low physiologically relevant concentrations of extracellular A{beta
关键词：amyloid fibrils ; late endosomes ; lysosomes ; plaques
