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The Journal of Neuroscience, July 15, 2001, 21(14):4987-4995

Dishevelled Regulates the Metabolism of Amyloid Precursor Protein via Protein Kinase C/Mitogen-Activated Protein Kinase and c-Jun Terminal Kinase

A. Mudher¹, S. Chapman¹, J. Richardson³, A. Asuni¹, G. Gibb¹, C. Pollard¹, R. Killick¹, T. Iqbal¹, L. Raymond², I. Varndell⁴, P. Sheppard⁴, A. Makoff², E. Gower³, P. E. Soden³, P. Lewis⁵, M. Murphy⁵, T. E. Golde⁵, H. T. Rupniak³, B. H. Anderton¹, and S. Lovestone^{1, 2}

Departments of ¹ Neuroscience and ² Psychiatry, Institute of Psychiatry, King's College London, London SE5 8AF, United Kingdom, ³ Glaxo Wellcome, Stevenage, Herts, SG1 2NY, United Kingdom, ⁴ Affiniti Research Products Limited, Mamhead, Exeter, EX6 8HD, United Kingdom, and ⁵ Mayo Clinic Jacksonville, Department of Neuroscience, Florida 32224

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 -secretase cleavage of APP, producing secreted APP (sAPP), and glycogen synthase kinase (GSK)-3 is known to increase tau phosphorylation. Both PKC and GSK-3 are components of the wnt signaling cascade. Here we demonstrate that overexpression of another member of this pathway, dishevelled (dvl-1), increases sAPP 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-3. Therefore, both APP metabolism and tau phosphorylation are potentially linked through wnt signaling.

Key words: dishevelled; Alzheimer's disease; amyloid precursor protein; PKC; JNK; GSK-3; tau; wnt

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21144987-09$05.00/0

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