| First Author | Killick R | Year | 2014 |
| Journal | Mol Psychiatry | Volume | 19 |
| Issue | 1 | Pages | 88-98 |
| PubMed ID | 23164821 | Mgi Jnum | J:241059 |
| Mgi Id | MGI:5897547 | Doi | 10.1038/mp.2012.163 |
| Citation | Killick R, et al. (2014) Clusterin regulates beta-amyloid toxicity via Dickkopf-1-driven induction of the wnt-PCP-JNK pathway. Mol Psychiatry 19(1):88-98 |
| abstractText | Although the mechanism of Abeta 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 Abeta neurotoxicity. We asked if clusterin, known to be regulated by wnt, is part of an Abeta/Dkk1 neurotoxic pathway. Knockdown of clusterin in primary neurons reduced Abeta toxicity and DKK1 upregulation and, conversely, Abeta 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 Abeta mediates neurotoxicity, we measured the effects of Abeta 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 (Kruppel-like factor-10) that, when individually silenced, protected against Abeta neurotoxicity and/or tau phosphorylation. Neuronal overexpression of Dkk1 in transgenic mice mimicked this Abeta-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 Abeta-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 Abeta 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 Abeta in neurodegenerative diseases. |
