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

Research output: Contribution to journalArticlepeer-review

111 Scopus citations

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 α-secretase cleavage of APP, producing secreted APP (sAPPα), and glycogen synthase kinase (GSK)-3β is known to increase tau phosphorylation. Both PKC and GSK-3β are components of the wnt signaling cascade. Here we demonstrate that overexpression of another member of this pathway, dishevelled (dvl-1), increases sAPPα 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-3β. 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
DOIs
StatePublished - Jul 15 2001

Keywords

  • Alzheimer's disease
  • Amyloid precursor protein
  • Dishevelled
  • GSK-3
  • JNK
  • PKC
  • Tau
  • Wnt

ASJC Scopus subject areas

  • Neuroscience (all)

Fingerprint

Dive into the research topics of 'Dishevelled regulates the metabolism of amyloid precursor protein via protein kinase C/mitogen-activated protein kinase and c-jun terminal kinase'. Together they form a unique fingerprint.

Cite this