RGD Reference Report - Clusterin regulates ß-amyloid toxicity via Dickkopf-1-driven induction of the wnt-PCP-JNK pathway. - Rat Genome Database

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

Authors: 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  Simons, J Paul  Lovestone, Simon 
Citation: Killick R, etal., Mol Psychiatry. 2014 Jan;19(1):88-98. doi: 10.1038/mp.2012.163. Epub 2012 Nov 20.
RGD ID: 12903240
Pubmed: PMID:23164821   (View Abstract at PubMed)
PMCID: PMC3873038   (View Article at PubMed Central)
DOI: DOI:10.1038/mp.2012.163   (Journal Full-text)

Although the mechanism of Aß 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 Aß neurotoxicity. We asked if clusterin, known to be regulated by wnt, is part of an Aß/Dkk1 neurotoxic pathway. Knockdown of clusterin in primary neurons reduced Aß toxicity and DKK1 upregulation and, conversely, Aß 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 Aß mediates neurotoxicity, we measured the effects of Aß 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 Aß neurotoxicity and/or tau phosphorylation. Neuronal overexpression of Dkk1 in transgenic mice mimicked this Aß-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 Aß-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 Aß 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 Aß in neurodegenerative diseases.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
negative regulation of neuron apoptotic process involved_inIGIComplexPortal:CPX-1120 more ...12903240PMID:23164821ARUK-UCL 
positive regulation of gene expression involved_inIGIComplexPortal:CPX-1120 more ...12903240; 12903240PMID:23164821ARUK-UCL 
regulation of neuron apoptotic process involved_inIGIComplexPortal:CPX-1120 more ...12903240PMID:23164821ARUK-UCL 

Objects Annotated

Genes (Rattus norvegicus)
Clu  (clusterin)
Egr1  (early growth response 1)
Tp53  (tumor protein p53)

Objects referenced in this article
Gene Dkk1 dickkopf WNT signaling pathway inhibitor 1 Rattus norvegicus
Gene Fos Fos proto-oncogene, AP-1 transcription factor subunit Rattus norvegicus
Gene Nab2 Ngfi-A binding protein 2 Rattus norvegicus

Additional Information