Dimerization leads to changes in APP (amyloid precursor protein) trafficking mediated by LRP1 and SorLA
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Dimerization leads to changes in APP (amyloid precursor protein) trafficking mediated by LRP1 and SorLA. / Eggert, Simone; Gonzalez, A C; Thomas, C; Schilling, S; Schwarz, S M; Tischer, C; Adam, V; Strecker, P; Schmidt, V; Willnow, T E; Hermey, G; Pietrzik, C U; Koo, E H; Kins, Stefan.
In: CELL MOL LIFE SCI, Vol. 75, No. 2, 01.2018, p. 301-322.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Dimerization leads to changes in APP (amyloid precursor protein) trafficking mediated by LRP1 and SorLA
AU - Eggert, Simone
AU - Gonzalez, A C
AU - Thomas, C
AU - Schilling, S
AU - Schwarz, S M
AU - Tischer, C
AU - Adam, V
AU - Strecker, P
AU - Schmidt, V
AU - Willnow, T E
AU - Hermey, G
AU - Pietrzik, C U
AU - Koo, E H
AU - Kins, Stefan
PY - 2018/1
Y1 - 2018/1
N2 - 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.
AB - 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.
KW - Journal Article
U2 - 10.1007/s00018-017-2625-7
DO - 10.1007/s00018-017-2625-7
M3 - SCORING: Journal article
C2 - 28799085
VL - 75
SP - 301
EP - 322
JO - CELL MOL LIFE SCI
JF - CELL MOL LIFE SCI
SN - 1420-682X
IS - 2
ER -
