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

Dishevelled regulates the metabolism of amyloid precursor protein via protein kinase C/Mitogen-activated protein kinase and c-Jun terminal kinase
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. 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.
dishevelled, alzheimer’s disease, amyloid precursorprotein, PKC, JNK, GSK-3, tau, wnt
0270-6474
4987-4995
Mudher, A.
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Chapman, S.
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Richardson, J.
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Asuni, A.
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Gibb, G.
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Pollard, C.
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Killick, R.
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Iqbal, T.
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Raymond, L.
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Vamdell, I.
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Sheppard, P.
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Makoff, A.
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Gower, E.
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Soden, P.E.
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Lewis, P.
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Murphy, M.
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Golde, T.E.
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Rupniak, H.T.
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Anderton, B.H.
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Lovestone, S.
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Mudher, A.
ce0ccb35-ac49-4b6c-92b4-8dd5e78ac119
Chapman, S.
fd50954c-e7e3-4971-8b96-a08c683b92d8
Richardson, J.
e25f154e-4705-443e-a996-58e774c54b70
Asuni, A.
d24f58c6-64e6-414a-a589-d6b988b1135b
Gibb, G.
5329693e-3d90-42d6-b743-4931c2966628
Pollard, C.
b52a8de5-8ddd-4bc8-8069-453099aa14da
Killick, R.
b502e004-36a7-428c-a82e-20f6582336f7
Iqbal, T.
d70d491e-f68f-4f47-adaf-4ffc83ceddbe
Raymond, L.
ece90fee-0b27-42ab-a100-4a1503e871ba
Vamdell, I.
37467cb6-b4d9-43fc-92a0-4b781cf8eb53
Sheppard, P.
f6e58291-4de0-4e50-8faf-dec6b0509f58
Makoff, A.
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Gower, E.
23bf1464-2783-4dd1-91c9-c725aa8a7a6c
Soden, P.E.
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Lewis, P.
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Murphy, M.
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Golde, T.E.
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Rupniak, H.T.
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Anderton, B.H.
7b040dc9-263d-4de6-820c-1ff7f5bba7c9
Lovestone, S.
482e0c1a-10cf-45fb-8631-bf32ca331104

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.

Record type: Article

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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Published date: 15 July 2001
Keywords: dishevelled, alzheimer’s disease, amyloid precursorprotein, PKC, JNK, GSK-3, tau, wnt

Identifiers

Local EPrints ID: 24204
URI: http://eprints.soton.ac.uk/id/eprint/24204
ISSN: 0270-6474
PURE UUID: 1cc69b65-b8b5-4ee1-815a-b8bad8c04b28

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Date deposited: 28 Mar 2006
Last modified: 15 Mar 2024 06:53

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Contributors

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

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