title: Altered subcellular distribution of the Alzheimer's amyloid precursor protein under stress conditions.
abstract: Altered metabolism of the Alzheimer's amyloid precursor protein (APP) appears to be a key event in the pathogenesis of Alzheimer's disease (AD), and both altered phosphorylation and oxidative stress appear to affect the production of the toxic Abeta fragment. Our results show that altered processing of APP was observed under conditions of stress induced by sodium azide in the presence of 2-deoxy-D-glucose (2DG). As previously reported, the production of the secreted fragment of APP (sAPP) was inhibited. Using APP-GFP fusion proteins, we show that 2DG causes the accumulation/delay of APP in the endoplasmic reticulum (ER)/Golgi (G). The 751 isoform accumulated preferentially in the G, whereas the 695 isoform was blocked preferentially at the ER. This effect was augmented in the presence of sodium azide. APP subcellular distribution was also affected at the plasma membrane. The involvement of protein phosphorylation in APP subcellular localization was reinforced by the effect of drugs, such as phorbol 12-myristate 13-acetate (PMA), since APP was completely depleted from the membrane in the presence of 2DG and PMA. Thus, the hypothesis that APP is processed in a phosphorylation-dependent manner and that this may be of clinical relevance appears to hold true even under stress conditions. Our results provide evidence for a role of protein phosphorylation in APP sorting under stress conditions and contribute to the understanding of the molecular basis of AD.
authors.affiliation: Neuroscience Laboratory, Centre for Cell Biology, University of Aveiro, Aveiro, Portugal.
authors.forename: Sara C T S
authors.initials: SC
authors.lastname: Domingues
authors.forename: Ana Gabriela
authors.initials: AG
authors.lastname: Henriques
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Wu
authors.forename: Edgar F
authors.initials: EF
authors.lastname: Da Cruz e Silva
authors.forename: Odete A B
authors.initials: OA
authors.lastname: Da Cruz e Silva
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003847:Deoxyglucose / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005786:Gene Expression Regulation; D006056:Golgi Apparatus / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D018384:Oxidative Stress; D010766:Phosphorylation; D020033:Protein Isoforms; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D016564:Amyloid beta-Protein Precursor; D020033:Protein Isoforms; D049452:Green Fluorescent Proteins; D003847:Deoxyglucose; D013755:Tetradecanoylphorbol Acetate