Chafekar Sidhartha M, Baas Frank, Scheper Wiep
Neurogenetics Laboratory Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
Biochim Biophys Acta. 2008 Sep;1782(9):523-31. doi: 10.1016/j.bbadis.2008.06.003. Epub 2008 Jun 13.
Alzheimer's disease (AD) is characterized by the aggregation and subsequent deposition of misfolded beta-amyloid (Abeta) peptide. Previous studies show that aggregated Abeta 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 Abeta1-42 and demonstrate that Abeta1-42 oligomers readily enter both HeLa and differentiated SKNSH cells whereas fibrillar Abeta1-42 is not internalized. Oligomeric Abeta1-42 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 Abeta toxicity.
阿尔茨海默病（AD）的特征是错误折叠的β-淀粉样蛋白（Aβ）肽聚集并随后沉积。先前的研究表明，聚集的Aβ在寡聚体形式下比纤维状形式更具毒性，并且每种聚集形式都会激活细胞中的特定分子途径。我们假设寡聚体和纤维之间的这些差异与其对细胞内空间的不同可及性有关。为此，我们使用了荧光标记的Aβ1-42，并证明Aβ1-42寡聚体很容易进入HeLa细胞和分化的SKNSH细胞，而纤维状Aβ1-42则不会被内化。寡聚体Aβ1-42通过内吞过程被内化并转运到溶酶体。摄取的抑制特异性地抑制寡聚体但不抑制纤维的毒性。我们的研究表明，寡聚体的选择性摄取是寡聚体特异性Aβ毒性的一个决定因素。
