Mudher, A., Chapman, S., Richardson, J., Asuni, A., Gibb, G., Pollard, C., Killick, R., Iqbal, T., Raymond, L., Vamdell, I., Sheppard, P., Makoff, A., Gower, E., Soden, P.E., Lewis, P., Murphy, M., Golde, T.E., Rupniak, H.T., Anderton, B.H. and Lovestone, S. (2001) Dishevelled regulates the metabolism of amyloid precursor protein via protein kinase C/Mitogen-activated protein kinase and c-Jun terminal kinase. Journal of Neuroscience, 21 (14), 4987-4995.
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 a-secretase cleavage of APP, producing secreted APP (sAPPa), and glycogen synthasekinase (GSK)-3b is known to increase tau phosphorylation. Both PKC and GSK-3b are components of the wnt signaling cascade. Here we demonstrate that overexpression of another member of this pathway, dishevelled (dvl-1), increasess APPa 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 p38MAP kinase. These data position dvl-1 upstream of both PKCand JNK, thereby explaining the previously observed dual signaling action of dvl-1. Furthermore, we show that human dvl-1and wnt-1 also reduce the phosphorylation of tau by GSK-3b. Therefore, both APP metabolism and tau phosphorylation are potentially linked through wnt signaling.
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