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

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. P rotein kinase C (PKC) is known to increase non-amyloidogenic alpha -secreta se cleavage of APP, producing secreted APP (sAPP alpha), and glycogen synth ase 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 demonst rate that overexpression of another member of this pathway, dishevelled (dv l-1), increases sAPP alpha production. The dishevelled action on APP is med iated via both c-jun terminal kinase (JNK) and protein kinase C (PKC)/mitog en-activated protein (MAP) kinase but not via p38 MAP kinase. These data po sition dvl-1 upstream of both PKC and JNK, thereby explaining the previousl y 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. There fore, both APP metabolism and tau phosphorylation are potentially linked th rough wnt signaling.