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Dimerization leads to changes in APP (amyloid precursor protein) trafficking mediated by LRP1 and SorLA

Item Type:Article
Title:Dimerization leads to changes in APP (amyloid precursor protein) trafficking mediated by LRP1 and SorLA
Creators Name:Eggert, S. and Gonzalez, A.C. and Thomas, C. and Schilling, S. and Schwarz, S.M. and Tischer, C. and Adam, V. and Strecker, P. and Schmidt, V. and Willnow, T.E. and Hermey, G. and Pietrzik, C.U. and Koo, E.H. and Kins, Stefan
Abstract:Proteolytic cleavage of the amyloid precursor protein (APP) byα-, β- and γ-secretases is a determining factor in Alzheimer's disease (AD). Imbalances in the activity of all three enzymes can result in alterations towards pathogenic A{beta} production. Proteolysis of APP is strongly linked to its subcellular localization as the secretases involved are distributed in different cellular compartments. APP has been shown to dimerize in cis-orientation, affecting A{beta} production. This might be explained by different substrate properties defined by the APP oligomerization state or alternatively by altered APP monomer/dimer localization. We investigated the latter hypothesis using two different APP dimerization systems in HeLa cells. Dimerization caused a decreased localization of APP to the Golgi and at the plasma membrane, whereas the levels in the ER and in endosomes were increased. Furthermore, we observed via live cell imaging and biochemical analyses that APP dimerization affects its interaction with LRP1 and SorLA, suggesting that APP dimerization modulates its interplay with sorting molecules and in turn its localization and processing. Thus, pharmacological approaches targeting APP oligomerization properties might open novel strategies for treatment of AD.
Keywords:APP Dimerization, APP Processing, APP Trafficking, APP Transport, Alzheimer's Disease, Animals, Mice
Source:Cellular and Molecular Life Sciences
ISSN:1420-682X
Publisher:Springer (Switzerland)
Volume:75
Number:2
Page Range:301-322
Date:January 2018
Official Publication:https://doi.org/10.1007/s00018-017-2625-7
PubMed:View item in PubMed

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