Dishevelled regulates the metabolism of amyloid precursor protein via protein kinase C/mitogen-activated protein kinase and c-Jun terminal kinase.

A Mudher, S Chapman, J Richardson, A Asuni, G Gibb, C Pollard, R Killick, T Iqbal, L Raymond, I Varndell, P Sheppard, A Makoff, E Gower, P E Soden, P Lewis, M Murphy, T E Golde, H T Rupniak, B H Anderton, S Lovestone

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113 Citations (Scopus)

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 (sAPP alpha), and glycogen synthase kinase (GSK)-3 beta is known to increase tau phosphorylation. Both PKC and GSK-3 beta are components of the wnt signaling cascade. Here we demonstrate that overexpression of another member of this pathway, dishevelled (dvl-1), increases sAPP alpha 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 beta. Therefore, both APP metabolism and tau phosphorylation are potentially linked through wnt signaling.
Original languageEnglish
Pages (from-to)4987 - 4995
Number of pages9
JournalJournal of Neuroscience
Volume21
Issue number14
Publication statusPublished - 15 Jul 2001

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