Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is associated with neuronal degeneration in Alzheimer's brain

Siena Biotech, 53100 Siena, Italy.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 07/2004; 24(26):6021-7. DOI: 10.1523/JNEUROSCI.1381-04.2004
Source: PubMed


We used primary cultures of cortical neurons to examine the relationship between beta-amyloid toxicity and hyperphosphorylation of the tau protein, the biochemical substrate for neurofibrillary tangles of Alzheimer's brain. Exposure of the cultures to beta-amyloid peptide (betaAP) induced the expression of the secreted glycoprotein Dickkopf-1 (DKK1). DKK1 negatively modulates the canonical Wnt signaling pathway, thus activating the tau-phosphorylating enzyme glycogen synthase kinase-3beta. DKK1 was induced at late times after betaAP exposure, and its expression was dependent on the tumor suppressing protein p53. The antisense induced knock-down of DKK1 attenuated neuronal apoptosis but nearly abolished the increase in tau phosphorylation in betaAP-treated neurons. DKK1 was also expressed by degenerating neurons in the brain from Alzheimer's patients, where it colocalized with neurofibrillary tangles and distrophic neurites. We conclude that induction of DKK1 contributes to the pathological cascade triggered by beta-amyloid and is critically involved in the process of tau phosphorylation.

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Available from: Andrea Caricasole, Aug 06, 2014
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    • "Please cite this article in press as: Patel, A.K., et al., Activation of Wnt/b-catenin signaling in Muller glia protects photoreceptors in a mouse model of inherited retinal degeneration, Neuropharmacology (2014), 2013; Sanges et al., 2013), and induced functional improvement in a spinal cord injury model (Suh et al., 2011). Additionally, b-catenin overexpression, which activates Wnt signaling, reduced apoptosis in a chicken ethanol neurodegeneration model (Flentke et al., 2014), and blocking Wnt inhibitors in several different in vitro and in vivo models of neuronal injury significantly reduced apoptosis (Caricasole et al., 2004; Toledo et al., 2008). Downregulation of Wnt signaling, by pharmacologic inhibition or overexpression of the antagonists Axin2 or Dkk1, promoted neurodegeneration in cellular and animal models of Alzheimer's disease (Toledo et al., 2008) and hippocampal neurons in vivo (Kim et al., 2011). "
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    ABSTRACT: The canonical Wnt/β-catenin ("Wnt") pathway is an essential signaling cascade in the embryonic central nervous system (CNS) that regulates neuronal differentiation and survival. Loss of Wnt signaling in developing and adult tissue has been implicated in numerous CNS diseases, but the precise role of Wnt in regulating neuronal survival, and how its absence could lead to disease, is not understood. In this study, we investigated the effect of Wnt activation on neuronal survival in the adult retina, and identified cellular and molecular mediators. Pan-retinal Wnt signaling activation using Wnt3a induced functional and morphological rescue of photoreceptor neurons in the rd10 mouse model of retinal degeneration. Furthermore, Wnt activation using constitutively active β-catenin specifically targeted to Muller glia increased photoreceptor survival and reduced markers of glial and neuronal remodeling. Wnt-induced photoreceptor protection was associated with elevated levels of prosurvival protein Stat3, and was reduced by shRNA-mediated knock-down of Stat3, indicating cross-talk between pro-survival pathways. Therefore, these data increase our understanding of the role of Wnt signaling in the retina, and identify radial Muller glia as important cellular mediators of Wnt activity. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Neuropharmacology 12/2014; 91. DOI:10.1016/j.neuropharm.2014.11.015 · 5.11 Impact Factor
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    • "In AD brains, a marked decrease in β-catenin levels (Zhang et al., 1998) and increase in expression of the Wnt/β-catenin signaling antagonist Dickkopf-1 (Dkk-1) (Caricasole et al., 2004) have been observed. Additionally, common genetic variations in the low-density lipoprotein receptor-related protein 6 (LRP6), a co-receptor for Wnt/β-catenin signaling , have been associated with late-onset AD (De Ferrari et al., 2007) and its expression in AD is strongly downregulated (Liu et al., 2014). "
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    ABSTRACT: Amyloid-β (Aβ) oligomers are a key factor in Alzheimer's disease (AD)-associated synaptic dysfunction. Aβ oligomers block the induction of hippocampal long-term potentiation (LTP) in rodents. The activation of Wnt signaling prevents Aβ oligomer-induced neurotoxic effects. The compound WASP-1 (Wnt-activating small molecule potentiator-1), has been described as a synergist of the ligand Wnt-3a, enhancing the activation of Wnt/β-catenin signaling. Herein, we report that WASP-1 administration successfully rescued Aβ-induced synaptic impairments both in vitro and in vivo. The activation of canonical Wnt/β-catenin signaling by WASP-1 increased synaptic transmission and rescued hippocampal LTP impairments induced by Aβ oligomers. Additionally, intra-hippocampal administration of WASP-1 to the double transgenic APPswe/PS1dE9 mouse model of AD prevented synaptic protein loss and reduced tau phosphorylation levels. Moreover, we found that WASP-1 blocked Aβ aggregation in vitro and reduced pathological tau phosphorylation in vivo. These results indicate that targeting canonical Wnt signaling with WASP-1 could have value for treating AD. Copyright © 2014. Published by Elsevier Inc.
    Experimental Neurology 11/2014; 264. DOI:10.1016/j.expneurol.2014.11.005 · 4.70 Impact Factor
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    • "In addition, the levels of b-catenin are significantly reduced in AD individuals bearing presenilin-1 mutations (Nishimura et al., 1999). Conversely, Dickkopf-1, a wellknown antagonist of the Wnt pathway, is increased in AD brains, upregulated by Ab treatment, and associated with Ab-mediated synaptic loss (Caricasole et al., 2004; Purro et al., 2012). Glycogen synthase kinase 3 (GSK3), which is negatively regulated by LRP6-mediated Wnt signaling, plays a central role in AD and its misregulation accounts for several pathological hallmarks of the disease, including hyperphosphorylation of tau and amyloid plaque formation (Hooper et al., 2008). "
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    ABSTRACT: Alzheimer's disease (AD) is an age-related neurological disorder characterized by synaptic loss and dementia. The low-density lipoprotein receptor-related protein 6 (LRP6) is an essential coreceptor for Wnt signaling, and its genetic variants have been linked to AD risk. Here we report that neuronal LRP6-mediated Wnt signaling is critical for synaptic function and cognition. Conditional deletion of Lrp6 gene in mouse forebrain neurons leads to age-dependent deficits in synaptic integrity and memory. Neuronal LRP6 deficiency in an amyloid mouse model also leads to exacerbated amyloid pathology due to increased APP processing to amyloid-β. In humans, LRP6 and Wnt signaling are significantly downregulated in AD brains, likely by a mechanism that depends on amyloid-β. Our results define a critical pathway in which decreased LRP6-mediated Wnt signaling, synaptic dysfunction, and elevated Aβ synergistically accelerate AD progression and suggest that restoring LRP6-mediated Wnt signaling can be explored as a viable strategy for AD therapy.
    Neuron 09/2014; 84(1). DOI:10.1016/j.neuron.2014.08.048 · 15.05 Impact Factor
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