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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.

Type

Journal article

Journal

J Neurosci

Publication Date

15/07/2001

Volume

21

Pages

4987 - 4995

Keywords

Adaptor Proteins, Signal Transducing, Alzheimer Disease, Amyloid Precursor Protein Secretases, Amyloid beta-Protein Precursor, Aspartic Acid Endopeptidases, Calcium-Calmodulin-Dependent Protein Kinases, Cell Line, Dishevelled Proteins, Endopeptidases, Gene Expression, Glycogen Synthase Kinase 3, Glycogen Synthase Kinases, Humans, JNK Mitogen-Activated Protein Kinases, Kidney, Mitogen-Activated Protein Kinases, Mutation, Phosphoproteins, Phosphorylation, Protein Kinase C, Proteins, Proto-Oncogene Proteins, Recombinant Fusion Proteins, Signal Transduction, Transfection, Wnt Proteins, Wnt1 Protein, Zebrafish Proteins, tau Proteins