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Clusterin regulates beta-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, AROCKIA; 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, Simon

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


Authors

R. Killick

E. M. Ribe

R. Al-Shawi

B. Malik

C. Hooper

C. Fernandes

R. Dobson

P. M. Nolan

S. Furney

K. Lin

G. Breen

R. Wroe

A .W.M. To

K. Leroy

M. Causevic

A. Usardi

M. Robinson

W. Noble

R. Williamson

K. Lunnon

S. Kellie

C. H. Reynolds

C. Bazenet

A. Hodges

J-P Brion

J. Stephenson

J. Paul Simons

Simon Lovestone



Abstract

Although the mechanism of Abaction in the pathogenesis of Alzheimer’s disease (AD) has remained elusive, it is known to increasethe expression of the antagonist of canonical wnt signalling, Dickkopf-1 (Dkk1), whereas the silencing ofDkk1blocks Abneurotoxicity. We asked if clusterin, known to be regulated by wnt, is part of an Ab/Dkk1 neurotoxic pathway. Knockdown ofclusterin in primary neurons reduced Abtoxicity andDKK1upregulation and, conversely, Abincreased intracellular clusterin anddecreased clusterin protein secretion, resulting in the p53-dependent induction ofDKK1. To further elucidate how the clusterin-dependent induction of Dkk1 by Abmediates neurotoxicity, we measured the effects of Aband Dkk1 protein on whole-genomeexpression in primary neurons, finding a common pathway suggestive of activation of wnt–planar cell polarity (PCP)–c-JunN-terminal kinase (JNK) signalling leading to the induction of genes includingEGR1(early growth response-1),NAB2(Ngfi-A-binding protein-2) andKLF10(Kru ̈ppel-like factor-10) that, when individually silenced, protected against Abneurotoxicity and/or tauphosphorylation. Neuronal overexpression of Dkk1 in transgenic mice mimicked this Ab-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 Ab-based mouse model of AD and in AD brain, but not in a tau-based mouse model or infrontotemporal dementia brain. Thus, we have identified a pathway whereby Abinduces a clusterin/p53/Dkk1/wnt–PCP–JNKpathway, which drives the upregulation of several genes that mediate the development of AD-like neuropathologies, therebyproviding new mechanistic insights into the action of Abin neurodegenerative diseases.

Journal Article Type Article
Acceptance Date Oct 9, 2012
Online Publication Date Nov 20, 2012
Publication Date Jan 1, 2014
Deposit Date May 17, 2018
Publicly Available Date Aug 19, 2020
Journal Molecular Psychiatry
Print ISSN 1359-4184
Electronic ISSN 1476-5578
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 19
Issue 1
Pages 88-98
DOI https://doi.org/10.1038/mp.2012.163
Public URL https://nottingham-repository.worktribe.com/output/1123286
Publisher URL https://www.nature.com/articles/mp2012163
PMID 00032896

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