title: Clusterin regulates β-amyloid toxicity via Dickkopf-1-driven induction of the wnt-PCP-JNK pathway.
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.
authors.affiliation: King's College London, Institute of Psychiatry, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Killick
authors.affiliation: King's College London, Institute of Psychiatry, London, UK.
authors.forename: E M
authors.initials: EM
authors.lastname: Ribe
authors.affiliation: Division of Medicine and Centre for Biomedical Science, University College London, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Al-Shawi
authors.affiliation: King's College London, Institute of Psychiatry, London, UK.
authors.forename: B
authors.initials: B
authors.lastname: Malik
authors.affiliation: King's College London, Institute of Psychiatry, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Hooper
authors.affiliation: King's College London, Institute of Psychiatry, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Fernandes
authors.affiliation: King's College London, Institute of Psychiatry, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Dobson
authors.affiliation: MRC Harwell, Mammalian Genetics Unit, Harwell Science and Innovation Campus, Oxfordshire, UK.
authors.forename: P M
authors.initials: PM
authors.lastname: Nolan
authors.affiliation: King's College London, Institute of Psychiatry, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Lourdusamy
authors.affiliation: King's College London, Institute of Psychiatry, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Furney
authors.affiliation: King's College London, Institute of Psychiatry, London, UK.
authors.forename: K
authors.initials: K
authors.lastname: Lin
authors.affiliation: King's College London, Institute of Psychiatry, London, UK.
authors.forename: G
authors.initials: G
authors.lastname: Breen
authors.affiliation: King's College London, Institute of Psychiatry, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Wroe
authors.affiliation: King's College London, Institute of Psychiatry, London, UK.
authors.forename: A W M
authors.initials: AW
authors.lastname: To
authors.affiliation: Université Libre de Bruxelles, Faculté de Médecine, Brussels, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: Leroy
authors.affiliation: King's College London, Institute of Psychiatry, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Causevic
authors.affiliation: King's College London, Institute of Psychiatry, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Usardi
authors.affiliation: King's College London, Institute of Psychiatry, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Robinson
authors.affiliation: King's College London, Institute of Psychiatry, London, UK.
authors.forename: W
authors.initials: W
authors.lastname: Noble
authors.affiliation: King's College London, Institute of Psychiatry, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Williamson
authors.affiliation: Division of Medicine and Centre for Biomedical Science, University College London, London, UK.
authors.forename: K
authors.initials: K
authors.lastname: Lunnon
authors.affiliation: University of Queensland, School of Chemistry and Molecular Biosciences, Brisbane, Queensland, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Kellie
authors.affiliation: King's College London, Institute of Psychiatry, London, UK.
authors.forename: C H
authors.initials: CH
authors.lastname: Reynolds
authors.affiliation: King's College London, Institute of Psychiatry, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Bazenet
authors.affiliation: King's College London, Institute of Psychiatry, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Hodges
authors.affiliation: Université Libre de Bruxelles, Faculté de Médecine, Brussels, Belgium.
authors.forename: J-P
authors.initials: JP
authors.lastname: Brion
authors.affiliation: King's College London, Institute of Psychiatry, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Stephenson
authors.affiliation: Division of Medicine and Centre for Biomedical Science, University College London, London, UK.
authors.forename: J Paul
authors.initials: JP
authors.lastname: Simons
authors.affiliation: King's College London, Institute of Psychiatry, London, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Lovestone
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D051152:Clusterin / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D051152:Clusterin; C501126:DKK1 protein, human; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D051153:Wnt Proteins