TY - JOUR
T1 - Dishevelled regulates the metabolism of amyloid precursor protein via protein kinase C/mitogen-activated protein kinase and c-jun terminal kinase
AU - Mudher, A.
AU - Chapman, S.
AU - Richardson, J.
AU - Asuni, A.
AU - Gibb, G.
AU - Pollard, C.
AU - Killick, R.
AU - Iqbal, T.
AU - Raymond, L.
AU - Varndell, I.
AU - Sheppard, P.
AU - Makoff, A.
AU - Gower, E.
AU - Soden, P. E.
AU - Lewis, P.
AU - Murphy, M.
AU - Golde, T. E.
AU - Rupniak, H. T.
AU - Anderton, B. H.
AU - Lovestone, S.
PY - 2001/7/15
Y1 - 2001/7/15
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - Amyloid precursor protein
KW - Dishevelled
KW - GSK-3
KW - JNK
KW - PKC
KW - Tau
KW - Wnt
UR - http://www.scopus.com/inward/record.url?scp=0035879075&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0035879075&partnerID=8YFLogxK
U2 - 10.1523/jneurosci.21-14-04987.2001
DO - 10.1523/jneurosci.21-14-04987.2001
M3 - Article
C2 - 11438574
AN - SCOPUS:0035879075
SN - 0270-6474
VL - 21
SP - 4987
EP - 4995
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 14
ER -