Oligomer-specific Aβ toxicity in cell models is mediated by selective uptake
Oligomer-specific Aβ toxicity in cell models is mediated by selective uptake
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DOI：
10.1016/j.bbadis.2008.06.003
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发表时间：
2008-09-01
影响因子：
6.2
通讯作者：
Scheper, Wiep
中科院分区：
文献类型：
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作者：
Chafekar, Sidhartha M.;Baas, Frank;Scheper, Wiep
阿尔茨海默病（AD）的特征在于错误折叠的β-淀粉样蛋白（A β）肽的聚集和随后的沉积。先前的研究表明，聚集的A β在寡聚体中比在纤维状形式中更具毒性，并且每种聚集形式都会激活细胞中的特定分子途径。我们推测寡聚体和原纤维之间的这些差异与它们对细胞内空间的不同可及性有关。为此，我们使用荧光标记的A β（1-42），并证明A β（1-42）寡聚体容易进入HeLa和分化的SK N SH细胞，而纤维状A β（1-42）不被内化。寡聚体A β（1-42）通过内吞过程内化并转运至溶酶体。抑制摄取特异性抑制低聚物，但不抑制原纤维毒性。我们的研究表明，寡聚体的选择性摄取是寡聚体特异性A β毒性的决定因素。(C)2008 Elsevier B. V.保留所有权利。
Alzheimer's disease (AD) is characterized by the aggregation and subsequent deposition of misfolded beta-amyloid (A beta) peptide. Previous studies show that aggregated A beta is more toxic in oligomeric than in fibrillar form, and that each aggregation form activates specific molecular pathways in the cell. We hypothesize that these differences between oligomers and fibrils are related to their different accessibility to the intracellular space. To this end we used fluorescently labelled A beta(1-42) and demonstrate that A beta(1-42) oligomers readily enter both HeLa and differentiated SK N SH cells whereas fibrillar A beta(1-42) is not internalized. Oligomeric A beta(1-42) is internalized by an endocytic process and is transported to the lysosomes. Inhibition of uptake specifically inhibits oligomer but not fibril toxicity. Our study indicates that selective uptake of oligomers is a determinant of oligomer specific A beta toxicity. (C) 2008 Elsevier B.V. All rights reserved.