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

Abstract

Proteolytic cleavage of the amyloid precursor protein (APP) by α-, 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 Aβ 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 Aβ 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.

Dysregulation of Neuronal Iron Homeostasis as an Alternative Unifying Effect of Mutations Causing Familial Alzheimer’s Disease

“…For example, APP can dimerize and transmembrane domain amino acid residues critical for this (and affecting γ-secretase cleavage) are mutated in EOfAD ( Yan et al, 2017 ) ( Figure 2 ). The dimerization of APP affects its interaction with the protein SORL1 and this influences the trafficking of APP from the ER to the plasma membrane ( Eggert et al, 2017 ) where FPN1 acts to export Fe 2+ . The most severe EOfAD mutations in APP (those with the earliest Alzheimer’s disease onset ages) affect the transmembrane domain amino acid residues critical for dimerization ( Figure 2 ).…”

Dimerization of sortilin regulates its trafficking to extracellular vesicles

“…Although multiple post-translational modifications, including phosphorylation ( 20 ), ubiquitination ( 21 , 22 ), and palmitoylation ( 23 ), regulate functions of sortilin, the mechanisms controlling sortilin trafficking have yet to be fully understood. Because the trafficking of receptors, such as G-protein–coupled receptors ( 24 ) and type I transmembrane proteins ( 25 , 26 ), can be regulated by dimerization, we hypothesized that dimerization is a major regulator of sortilin trafficking to EVs. Here, we provide the first evidence that sortilin forms homodimers, thereby facilitating its trafficking to EVs.…”

Reciprocal Modulation Between Amyloid Precursor Protein and Synaptic Membrane Cholesterol Revealed By Live Cell Imaging

“…Furthermore, the dimerization may also be accountable for the increase of surface APP after S inhibition. Interestingly, Eggert et al demonstrated that APP homodimers are preferentially located in the endosomes in HeLa cells, and that induced homodimerization reduces surface APP fraction (Eggert et al, 2017a). We postulate that the competition with intracellularly accumulated CTFs after S inhibition reduced APP homodimers and allowed more APP to reach the plasma membrane.…”