Abstract
Alzheimer's disease (AD) is a disorder of two pathologies: amyloid plaques, the core of which is a peptide derived from the amyloid precursor protein (APP), and neurofibrillary tangles composed of highly phosphorylated tau. Protein kinase C (PKC) is known to increase non-amyloidogenic alpha-secretase cleavage of APP, producing secreted APP (sAPPalpha), and glycogen synthase kinase (GSK)-3beta is known to increase tau phosphorylation. Both PKC and GSK-3beta are components of the wnt signaling cascade. Here we demonstrate that overexpression of another member of this pathway, dishevelled (dvl-1), increases sAPPalpha production. The dishevelled action on APP is mediated via both c-jun terminal kinase (JNK) and protein kinase C (PKC)/mitogen-activated protein (MAP) kinase but not via p38 MAP kinase. These data position dvl-1 upstream of both PKC and JNK, thereby explaining the previously observed dual signaling action of dvl-1. Furthermore, we show that human dvl-1 and wnt-1 also reduce the phosphorylation of tau by GSK-3beta. Therefore, both APP metabolism and tau phosphorylation are potentially linked through wnt signaling.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Alzheimer Disease / metabolism
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Amyloid Precursor Protein Secretases
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Amyloid beta-Protein Precursor / genetics
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Amyloid beta-Protein Precursor / metabolism*
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Aspartic Acid Endopeptidases
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Calcium-Calmodulin-Dependent Protein Kinases / genetics
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Cell Line
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Dishevelled Proteins
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Endopeptidases / metabolism
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Gene Expression
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Glycogen Synthase Kinase 3
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Glycogen Synthase Kinases
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Humans
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JNK Mitogen-Activated Protein Kinases
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Kidney / cytology
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Kidney / drug effects
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Kidney / metabolism
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Mitogen-Activated Protein Kinases / metabolism*
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Mutation
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Phosphoproteins / genetics
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Phosphoproteins / metabolism*
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Phosphoproteins / pharmacology
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Phosphorylation / drug effects
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Protein Kinase C / metabolism*
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Proteins / genetics
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Proteins / metabolism
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Proteins / pharmacology
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins / pharmacology
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Recombinant Fusion Proteins / pharmacology
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Transfection
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Wnt Proteins
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Wnt1 Protein
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Zebrafish Proteins*
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tau Proteins / genetics
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tau Proteins / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Amyloid beta-Protein Precursor
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DVL1 protein, human
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Dishevelled Proteins
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Phosphoproteins
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Proteins
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Proto-Oncogene Proteins
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Recombinant Fusion Proteins
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WNT1 protein, human
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Wnt Proteins
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Wnt1 Protein
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Zebrafish Proteins
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tau Proteins
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Glycogen Synthase Kinases
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Protein Kinase C
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Calcium-Calmodulin-Dependent Protein Kinases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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Glycogen Synthase Kinase 3
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Amyloid Precursor Protein Secretases
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Endopeptidases
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Aspartic Acid Endopeptidases
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BACE1 protein, human