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

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      Clusterin regulates β-amyloid toxicity via Dickkopf-1-driven induction of the wnt-PCP-JNK pathway.pdf (1.300Mb)
      Date
      2014-01
      Author
      Killick, R
      Ribe, EM
      Al-Shawi, R
      Malik, B
      Hooper, C
      Fernandes, C
      Dobson, R
      Nolan, PM
      Lourdusamy, A
      Furney, S
      Lin, K
      Breen, G
      Wroe, R
      To, AWM
      Leroy, K
      Causevic, M
      Usardi, A
      Robinson, M
      Noble, W
      Williamson, R
      Lunnon, K
      Kellie, S
      Reynolds, CH
      Bazenet, C
      Hodges, A
      Brion, J-P
      Stephenson, J
      Simons, JP
      Lovestone, S
      Date issued
      2014-01
      Journal
      Molecular Psychiatry
      Type
      Article
      Language
      en
      Publisher
      Nature Publishing Group
      Links
      https://www.ncbi.nlm.nih.gov/pubmed/23164821
      Rights
      This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/.
      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.
      Funders/Sponsor
      This study was funded by the Wellcome Trust, the NIHR BRC for Mental Health at the South London and Maudsley NHS Foundation Trust, the Alzheimer’s Society/BUPA Foundation, Alzheimer’s Research UK, the Fundacion Alfonso Martin Escudero and the Royal Free Hampstead NHS Trust.
      Description
      This is the final version of the article. Available from the publisher via the DOI in this record.
      Citation
      Vol. 19, pp. 88 - 98
      DOI
      https://doi.org/10.1038/mp.2012.163
      URI
      http://hdl.handle.net/10871/26491
      ISSN
      1476-5578
      PubMed Central ID
      PMC3873038
      PubMed ID
      23164821
      Other identifier
      mp2012163
      Collections
      • Institute of Biomedical & Clinical Science
      Place of publication
      England

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