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