Elsevier

Experimental Neurology

Volume 264, February 2015, Pages 14-25
Experimental Neurology

Regular Article
WASP-1, a canonical Wnt signaling potentiator, rescues hippocampal synaptic impairments induced by Aβ oligomers

https://doi.org/10.1016/j.expneurol.2014.11.005Get rights and content

Highlights

  • WASP-1 administration activates Wnt/β-catenin signaling.

  • WASP-1 rescues hippocampal LTP impairments induced by Aβ oligomers.

  • WASP-1 prevents synaptic protein loss in a mouse model of Alzheimer's disease.

  • WASP-1 reduces tau phosphorylation and Aβ aggregation.

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.

Introduction

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive deterioration of cognitive abilities, primarily caused by synaptic impairments and neuronal death in specific regions of the brain (Selkoe, 2001, Mattson, 2004). The accumulation of amyloid-β peptide (Aβ) in senile plaques primarily in the hippocampus, cortex and other brain areas linked to cognitive processes is considered one of the major pathological hallmarks of AD brains (Selkoe, 2001). Recent evidences indicate that soluble Aβ oligomers rather than plaques determine cognitive decline (Lacor et al., 2007, Shankar et al., 2007, Ferreira and Klein, 2011) and that the severity of dementia in AD patients is strongly correlated with the levels of soluble Aβ oligomers (Lue et al., 1999, McLean et al., 1999). Thus, the current view of AD considers Aβ oligomers to be a key factor in synaptic dysfunction linked to early stages of AD (Sakono and Zako, 2010). Indeed, Aβ oligomers isolated from AD brains can affect memory and disrupt hippocampal synaptic plasticity by inhibiting long-term potentiation (LTP) and increasing long-term depression (LTD) (Cleary et al., 2005, Shankar et al., 2008). However, Aβ-induced blockade of LTP can be overcome by inhibitors of Aβ oligomerization (Walsh et al., 2005), suggesting that AD cognitive impairment might be due to a direct effect of Aβ oligomers on the synaptic region. In fact, Aβ oligomers can affect excitatory synaptic transmission by reducing the amplitude of field excitatory postsynaptic potentials (fEPSP) at hippocampal synapses (Hermann et al., 2009, Cerpa et al., 2010).

Several lines of evidence indicate that the disruption of the Wnt signaling pathway contributes to AD pathogenesis (Inestrosa et al., 2000, Inestrosa and Varela-Nallar, 2014, De Ferrari et al., 2014). In the central nervous system, Wnt signaling plays an important role during development and in the maintenance and function of mature synapses (Ciani and Salinas, 2005, Inestrosa and Arenas, 2010). A number of Wnt pathways have been identified (Nusse, 2012). In particular, the canonical Wnt pathway, also called the Wnt/β-catenin pathway, is involved in the modulation of hippocampal synaptic plasticity (Chen et al., 2006, Cerpa et al., 2008).

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). Moreover, several studies have shown a relationship between the loss of Wnt/β-catenin signaling and an increase in Aβ-related neurotoxicity (De Ferrari et al., 2003, Alvarez et al., 2004, Inestrosa and Arenas, 2010). Specifically, loss of Wnt/β-catenin signaling increases neuronal vulnerability to Aβ-induced apoptosis (Zhang et al., 1998). Furthermore, Aβ exposure increases Dkk-1 expression (Caricasole et al., 2004, Purro et al., 2012), causing a reduction in the number of synapses and the size of pre- and post-synaptic compartments (Purro et al., 2012). However, the activation of Wnt/β-catenin signaling has been shown to protect against Aβ-induced cytotoxic effects (De Ferrari et al., 2003, Inestrosa et al., 2012, Inestrosa and Varela-Nallar, 2014). Indeed, incubation with the canonical ligand Wnt-3a prevents neuronal cell death induced by Aβ exposure (Alvarez et al., 2004). Additionally, treatment with lithium, a pharmacological activator of Wnt/β-catenin signaling, rescues memory loss and reduces Aβ deposition in the brain of a transgenic mouse model of AD (Toledo and Inestrosa, 2010). Moreover, treatment with lithium also rescues LTP deficits in a transgenic mouse conditionally overexpressing glycogen synthase kinase-3β (GSK-3β), a key enzyme that blocks Wnt/β-catenin signaling (Hooper et al., 2007).

These data suggest that direct stimulation of Wnt/β-catenin signaling or the inhibition of endogenous antagonists of this pathway could be a therapeutic approach to AD. Here, we studied the beneficial effects of WASP-1, a synthetic molecule that potentiates Wnt/β-catenin signaling (Beaumont et al., 2007, Vargas et al., 2014), on AD-related synapse damage. Through in vitro and in vivo approaches, we found that WASP-1 treatment effectively protects against Aβ-induced synaptic dysfunction.

Section snippets

Reagents

WASP-1 (2-(2,7-diethoxy-9H-fluoren-9-ylidene) hydrazine-carboximidamide) was obtained from Chemdiv, Inc. Synthetic Aβ1–42 peptide corresponding to the human Aβ wild-type peptide was obtained from Genemed Synthesis, Inc. Actinomycin-D and cycloheximide were purchased from Sigma-Aldrich, Inc. The polyclonal antibodies used are as follows: rabbit anti-phospho-β-catenin (Ser33/37/Thr41), mouse anti-β-actin and rabbit anti-synaptophysin (Cell Signaling Technology, Inc.), mouse anti-β-catenin (Santa

WASP-1 potentiates Wnt/β-catenin signaling and enhances synaptic plasticity

WASP-1 was identified as a transcriptional activator of β-catenin-dependent TopFlash reporter (Korinek et al., 1997), which in the presence of the Wnt-3a causes a synergistic increase in reporter activation (Beaumont et al., 2007). Interestingly, it appears that WASP-1 exerts its effect by acting downstream of Frizzled, the receptor for Wnt ligand (Beaumont et al., 2007). Here, we tested the effect of WASP-1 on the stability of β-catenin, a key protein in the canonical Wnt pathway. Using

Discussion

WASP-1 has previously been described as a small molecule that potentiates canonical Wnt/β-catenin signaling and enhances excitatory transmission in mature hippocampal synapses (Beaumont et al., 2007). Because the activation of Wnt/β-catenin signaling has a neuroprotective effect against Aβ-induced cytotoxic and synaptotoxic insults (Boonen et al., 2009, Cerpa et al., 2009, De Ferrari et al., 2014, Inestrosa and Varela-Nallar, 2014), here we tested the ability of WASP-1 to rescue the functional

Conclusions

In this study, we show that WASP-1 potentiates the activation of Wnt/β-catenin signaling in hippocampal neurons, thereby increasing normal synaptic function or rescuing Aβ-induced synaptic impairment (Fig. 7). Under normal conditions, WASP-1 can potentiate the effect of endogenous Wnt-3a and increase β-catenin stability. At the presynaptic terminal, WASP-1 enhances excitatory synaptic transmission by increasing the release of neurotransmitters. At the postsynaptic compartment, WASP-1 elicits a

Acknowledgments

This work was supported by grants from the Basal Center of Excellence in Science in Technology (CONICYT-PFB12/2007) and FONDECYT no. 1120156 to N.C.I.; FONDECYT no. 11090059, no. 1130614 and DIPUV CID 01/2006 to M.F.; a pre-doctoral fellowship from Fundación Gran Mariscal de Ayacucho to J.Y.V.; and pre-doctoral fellowships from CONICYT to J.A. and M.S.A. We thank Felipe Serrano for his help with Fig. 7.

References (73)

  • N. Gogolla et al.

    Wnt signaling mediates experience-related regulation of synapse numbers and mossy fiber connectivities in the adult hippocampus

    Neuron

    (2009)
  • D. Hermann et al.

    Synaptic transmission is impaired prior to plaque formation in amyloid precursor protein-overexpressing mice without altering behaviorally-correlated sharp wave-ripple complexes

    Neuroscience

    (2009)
  • U. Kuhnt et al.

    Interaction between paired-pulse facilitation and long-term potentiation in area CA1 of guinea-pig hippocampal slices: application of quantal analysis

    Neuroscience

    (1994)
  • C.C. Liu et al.

    Deficiency in LRP6-mediated Wnt signaling contributes to synaptic abnormalities and amyloid pathology in Alzheimer's disease

    Neuron

    (2014)
  • L.F. Lue et al.

    Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease

    Am. J. Pathol.

    (1999)
  • R.J. Racine et al.

    Long-term potentiation phenomena in the rat limbic forebrain

    Brain Res.

    (1983)
  • C.R. Raymond

    LTP forms 1, 2 and 3: different mechanisms for the “long” in long-term potentiation

    Trends Neurosci.

    (2007)
  • A. Ahmad-Annuar et al.

    Signaling across the synapse: a role for Wnt and Dishevelled in presynaptic assembly and neurotransmitter release

    J. Cell Biol.

    (2006)
  • M.S. Arrazola et al.

    Calcium/calmodulin-dependent protein kinase type IV is a target gene of the Wnt/beta-catenin signaling pathway

    J. Cell. Physiol.

    (2009)
  • C. Bonansco et al.

    Glutamate released spontaneously from astrocytes sets the threshold for synaptic plasticity

    Eur. J. Neurosci.

    (2011)
  • O. Bozdagi et al.

    Persistence of coordinated long-term potentiation and dendritic spine enlargement at mature hippocampal CA1 synapses requires N-cadherin

    J. Neurosci.

    (2010)
  • A. Caricasole et al.

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

    J. Neurosci.

    (2004)
  • W. Cerpa et al.

    The role of Wnt signaling in neuroprotection

    Drug News Perspect.

    (2009)
  • W. Cerpa et al.

    Wnt-5a occludes Abeta oligomer-induced depression of glutamatergic transmission in hippocampal neurons

    Mol. Neurodegener.

    (2010)
  • L. Ciani et al.

    WNTs in the vertebrate nervous system: from patterning to neuronal connectivity

    Nat. Rev. Neurosci.

    (2005)
  • L. Ciani et al.

    Wnt7a signaling promotes dendritic spine growth and synaptic strength through Ca(2)/calmodulin-dependent protein kinase II

    Proc. Natl. Acad. Sci. U. S. A.

    (2011)
  • A. Citri et al.

    Synaptic plasticity: multiple forms, functions, and mechanisms

    Neuropsychopharmacology

    (2008)
  • K.A. Clark et al.

    A comparison of paired-pulsed facilitation of AMPA and NMDA receptor-mediated excitatory postsynaptic currents in the hippocampus

    Exp. Brain Res.

    (1994)
  • J.P. Cleary et al.

    Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function

    Nat. Neurosci.

    (2005)
  • G.V. De Ferrari et al.

    Activation of Wnt signaling rescues neurodegeneration and behavioral impairments induced by beta-amyloid fibrils

    Mol. Psychiatry

    (2003)
  • G.V. De Ferrari et al.

    Common genetic variation within the low-density lipoprotein receptor-related protein 6 and late-onset Alzheimer's disease

    Proc. Natl. Acad. Sci. U. S. A.

    (2007)
  • G.V. De Ferrari et al.

    Wnt/beta-catenin signaling in Alzheimer's disease

    CNS Neurol. Disord. Drug Targets

    (2014)
  • M.C. Dinamarca et al.

    Amyloid-beta-Acetylcholinesterase complexes potentiate neurodegenerative changes induced by the Abeta peptide. Implications for the pathogenesis of Alzheimer's disease

    Mol. Neurodegener.

    (2010)
  • G.G. Farias et al.

    Wnt-7a induces presynaptic colocalization of alpha 7-nicotinic acetylcholine receptors and adenomatous polyposis coli in hippocampal neurons

    J. Neurosci.

    (2007)
  • J. Hardy et al.

    The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics

    Science

    (2002)
  • C. Hooper et al.

    Glycogen synthase kinase-3 inhibition is integral to long-term potentiation

    Eur. J. Neurosci.

    (2007)
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