Selivanova Alexandra, Winblad Bengt, Farmery Mark R, Dantuma Nico P, Ankarcrona Maria
Department of Neurobiology, Caring Sciences and Society (NVS), KI Alzheimer Disease Research Center, Karolinska Institutet, Novum 5th floor, S-141 57 Stockholm, Sweden.
Biochem Biophys Res Commun. 2006 Nov 10;350(1):220-6. doi: 10.1016/j.bbrc.2006.09.043. Epub 2006 Sep 18.
Sequential cleavage of the amyloid precursor protein (APP) by beta- and gamma-secretases results in the production of beta-amyloid peptide, which is a key determinant in Alzheimer's disease. Since several putative locations for gamma-secretase cleavage have been identified along the secretory pathway, trafficking of APP may be of importance for beta-amyloid peptide production. Here we have studied the role of retrograde transport in APP processing. We found that APP interacts with the beta subunit of the coatomer protein I (COPI) complex, which is involved in retrograde transport. In line with a role of retrograde trafficking in APP transport, inhibition of COPI-dependent transport altered APP trafficking, decreased APP cell surface expression, and coincided with a profound reduction in gamma-secretase cleavage. These results suggest that COPI-dependent retrograde transport is important for APP processing and influences production of beta-amyloid peptide.
淀粉样前体蛋白（APP）经β-分泌酶和γ-分泌酶的顺序切割会产生β-淀粉样肽，这是阿尔茨海默病的关键决定因素。由于已在分泌途径中确定了γ-分泌酶切割的几个假定位置，APP的运输对于β-淀粉样肽的产生可能很重要。在此，我们研究了逆行运输在APP加工中的作用。我们发现APP与参与逆行运输的外衣蛋白I（COPI）复合物的β亚基相互作用。与逆行运输在APP运输中的作用一致，抑制依赖COPI的运输改变了APP的运输，降低了APP在细胞表面的表达，同时γ-分泌酶切割也大幅减少。这些结果表明，依赖COPI的逆行运输对APP加工很重要，并影响β-淀粉样肽的产生。
