Clusterin regulates β-amyloid toxicity via Dickkopf-1-driven induction of the wnt-PCP-JNK pathway

Killick, R., Ribe, E. M., Al-Shawi, R., Malik, B., Hooper, C., Fernandes, C., Dobson, R., Nolan, P. M., Lourdusamy, A., Furney, S., Lin, K., Breen, G., Wroe, R., To, A. W. M., Leroy, K., Causevic, M., Usardi, A., Robinson, M., Noble, W., Williamson, R., Lunnon, K., Kellie, S., Reynolds, C. H., Bazenet, C., Hodges, A., Brion, J.-P., Stephenson, J., Paul Simons, J. and Lovestone, S. (2014) Clusterin regulates β-amyloid toxicity via Dickkopf-1-driven induction of the wnt-PCP-JNK pathway. Molecular Psychiatry, 19 1: 88-98. doi:10.1038/mp.2012.163


Author Killick, R.
Ribe, E. M.
Al-Shawi, R.
Malik, B.
Hooper, C.
Fernandes, C.
Dobson, R.
Nolan, P. M.
Lourdusamy, A.
Furney, S.
Lin, K.
Breen, G.
Wroe, R.
To, A. W. M.
Leroy, K.
Causevic, M.
Usardi, A.
Robinson, M.
Noble, W.
Williamson, R.
Lunnon, K.
Kellie, S.
Reynolds, C. H.
Bazenet, C.
Hodges, A.
Brion, J.-P.
Stephenson, J.
Paul Simons, J.
Lovestone, S.
Title Clusterin regulates β-amyloid toxicity via Dickkopf-1-driven induction of the wnt-PCP-JNK pathway
Journal name Molecular Psychiatry   Check publisher's open access policy
ISSN 1359-4184
1476-5578
Publication date 2014
Year available 2012
Sub-type Article (original research)
DOI 10.1038/mp.2012.163
Open Access Status DOI
Volume 19
Issue 1
Start page 88
End page 98
Total pages 11
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Collection year 2015
Language eng
Abstract Although the mechanism of Aβ action in the pathogenesis of Alzheimer's disease (AD) has remained elusive, it is known to increase the expression of the antagonist of canonical wnt signalling, Dickkopf-1 (Dkk1), whereas the silencing of Dkk1 blocks Aβ neurotoxicity. We asked if clusterin, known to be regulated by wnt, is part of an Aβ/Dkk1 neurotoxic pathway. Knockdown of clusterin in primary neurons reduced Aβ toxicity and DKK1 upregulation and, conversely, Aβ increased intracellular clusterin and decreased clusterin protein secretion, resulting in the p53-dependent induction of DKK1. To further elucidate how the clusterin-dependent induction of Dkk1 by Aβ mediates neurotoxicity, we measured the effects of Aβ and Dkk1 protein on whole-genome expression in primary neurons, finding a common pathway suggestive of activation of wnt-planar cell polarity (PCP)-c-Jun N-terminal kinase (JNK) signalling leading to the induction of genes including EGR1 (early growth response-1), NAB2 (Ngfi-A-binding protein-2) and KLF10 (Krüppel-like factor-10) that, when individually silenced, protected against Aβ neurotoxicity and/or tau phosphorylation. Neuronal overexpression of Dkk1 in transgenic mice mimicked this Aβ-induced pathway and resulted in age-dependent increases in tau phosphorylation in hippocampus and cognitive impairment. Furthermore, we show that this Dkk1/wnt-PCP-JNK pathway is active in an Aβ-based mouse model of AD and in AD brain, but not in a tau-based mouse model or in frontotemporal dementia brain. Thus, we have identified a pathway whereby Aβ induces a clusterin/p53/Dkk1/wnt-PCP-JNK pathway, which drives the upregulation of several genes that mediate the development of AD-like neuropathologies, thereby providing new mechanistic insights into the action of Aβ in neurodegenerative diseases.
Keyword Alzheimers
Amyloid
Clusterin
Dickkopf-1
Tau
wnt
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online: 20 November 2012.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Chemistry and Molecular Biosciences
 
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Created: Fri, 10 Jan 2014, 11:20:46 EST by Miss Abigail Downie on behalf of School of Chemistry & Molecular Biosciences