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

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.

Citation

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. .., Leroy, K., Causevic, M., Usardi, A., Robinson, M., Noble, W., Williamson, R., …Lovestone, S. (2014). Clusterin regulates beta-amyloid toxicity via Dickkopf-1-driven induction of the wnt-PCP-JNK pathway. Molecular Psychiatry, 19(1), 88-98. https://doi.org/10.1038/mp.2012.163

• 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