GGA1 overexpression attenuates amyloidogenic processing of the amyloid precursor protein in Niemann-Pick type C cells |
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Authors: | Marko Kosicek Patrick Wunderlich Jochen Walter Silva Hecimovic |
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Affiliation: | 1. Division of Molecular Medicine, Rudjer Boskovic Institute, Bijenicka 54, 10000 Zagreb, Croatia;2. Department of Neurology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany |
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Abstract: | Alzheimer’s disease (AD) and a rare inherited disorder of cholesterol transport, Niemann-Pick type C (NPC) share several similarities including aberrant APP processing and increased Aβ production. Previously, we have shown that the AD-like phenotype in NPC model cells involves cholesterol-dependent enhanced APP cleavage by β-secretase and accumulation of both APP and BACE1 within endocytic compartments. Since retrograde transport of BACE1 from endocytic compartments to the trans-Golgi network (TGN) is regulated by the Golgi-localized γ-ear containing ADP ribosylation factor-binding protein 1 (GGA1), we analyzed in this work a potential role of GGA1 in the AD-like phenotype of NPC1-null cells. Overexpression of GGA1 caused a shift in APP processing towards the non-amyloidogenic pathway by increasing the localization of APP at the cell surface. However, the observed effect appear to be independent on the subcellular localization and phosphorylation state of BACE1. These findings show that the AD-like phenotype of NPC model cells can be partly reverted by promoting a non-amyloidogenic processing of APP through the upregulation of GGA1 supporting its preventive role against AD. |
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Keywords: | Aβ, amyloid beta peptide AD, Alzheimer&rsquo s disease ADAM, A disintegrin and metalloproteinase APOE, apolipoprotein E APP, amyloid precursor protein BACE1, beta-secretase CHO, Chinese hamster ovary CTF, C-terminal fragment DN, dominant negative FA, formic acid GFP, green fluorescent protein GGA1, Golgi-localized γ-ear containing ADP ribosylation factor-binding protein 1 HEK, human embryonic kidney HRP, horseradish peroxidase NPC, Niemann-Pick type C PBS, phosphate buffer saline sAPP, soluble N-terminal fragment of amyloid precursor protein PAGE, polyacrylamide gel electrophoresis PVDF, polyvinylidene difluoride RIPA, radio-immunoprecipitation assay buffer SDS, sodium dodecyl sulfate SEAP, secreted alkaline phosphatase TfR, transferrin receptor TGN, trans-Golgi network wt, wild type |
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