Inhibition of Wnt signaling, modulation of Tau phosphorylation and induction of neuronal cell death by DKK1

Scali, Carla; Caraci, Filippo; Gianfriddo, Marco; Diodato, Enrica; Roncarati, Renza; Pollio, Giuseppe; Gaviraghi, G.; Copani, Agata; Nicoletti, Ferdinando; Terstappen, Georg C.; Caricasole, Andrea

doi:10.1016/j.nbd.2006.06.016

Cited by 116 publications

(80 citation statements)

References 69 publications

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“…In our system, Dkk1 reversibly affects the number of synapses without affecting programmed cell death. Interestingly, previous studies have indicated that increased Dkk1 levels contribute to cell death in cerebral ischemia (Cappuccio et al, 2005;Mastroiacovo et al, 2009), epilepsy (Busceti et al, 2007) and neurodegenerative diseases (Scali et al, 2006;Rosi et al, 2010). This apparent discrepancy could be explained by the low level and short-term treatment with Dkk1 used in our system.…”

Section: Discussionmentioning

confidence: 71%

The Secreted Wnt Antagonist Dickkopf-1 Is Required for Amyloid β-Mediated Synaptic Loss

Purro

Dickins²,

Salinas³

2012

J. Neurosci.

178

201

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Extensive evidence supports a central role for amyloid-␤ (A␤) in the pathogenesis of Alzheimer's disease (AD). Synaptic loss mediated by A␤ in early stages of the disease might contribute to cognitive impairments. However, little is known about the mechanism by which A␤ induces the loss of synapses. The expression of the Wnt antagonist Dickkopf-1 (Dkk1) is increased in brains of AD patients and in AD transgenic mouse models, suggesting that dysfunction of Wnt signaling could contribute to AD pathology. Here we report that acute exposure to A␤ oligomers induces Dkk1 expression together with the loss of synaptic sites. Importantly, Dkk1-neutralizing antibodies suppress A␤-induced synapse loss in mouse brain slices. In mature rat hippocampal neurons, Dkk1 decreases the number of synapses without affecting cell viability. Ultrastructural analyses revealed that Wnt blockade decreases the size of presynaptic and postsynaptic terminals. Time-lapse recordings of RFP-labeled stable synaptic sites demonstrate that Dkk1 induces the dispersal of synaptic components. These findings identify Dkk1 as a potential therapeutic target for the treatment of AD.

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Section: Discussionmentioning

confidence: 71%

The Secreted Wnt Antagonist Dickkopf-1 Is Required for Amyloid β-Mediated Synaptic Loss

Purro

Dickins²,

Salinas³

2012

J. Neurosci.

178

201

View full text Add to dashboard Cite

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“…It was also found that induction of Dickkopf protein 1 (DKK1), a Wnt pathway inhibitor (Krupnik et al, 1999), was associated with neurodegeneration in the brains of individuals with AD (Caricasole et al, 2004). Researchers demonstrated that, in the CA1 region of the rat hippocampus, systemic administration of lithium reversed local infusion of DKK1-induced neuronal cell death and astrocytosis (Scali et al, 2006). Lithium has further been shown to protect against Ab-induced ER stress and the subsequent activation of caspases and NF-kB in the hippocampus of rabbits .…”

Section: Admentioning

confidence: 99%

Therapeutic Potential of Mood Stabilizers Lithium and Valproic Acid: Beyond Bipolar Disorder

et al. 2013

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“…The GSK-3␤ activity could modulate the intrinsic apoptotic pathway by modifying, directly and/or indirectly, the expression of pro-and anti-apoptotic Bcl-2 family proteins (35)(36)(37). Thus, we have determined the possible variations in the expression of mRNAs coding for Bcl-2 proteins in 6-and 18-monthold WT and PS1ϫAPP tg mice.…”

Section: Age-dependent Modifications On the Gsk-3␤ Activity In Ps1ϫappmentioning

confidence: 99%

Age-dependent Accumulation of Soluble Amyloid β (Aβ) Oligomers Reverses the Neuroprotective Effect of Soluble Amyloid Precursor Protein-α (sAPPα) by Modulating Phosphatidylinositol 3-Kinase (PI3K)/Akt-GSK-3β Pathway in Alzheimer Mouse Model

Jiménez

Torres

Vizuete

et al. 2011

Journal of Biological Chemistry

175

157

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Neurotrophins, activating the PI3K/Akt signaling pathway, control neuronal survival and plasticity. Alterations in NGF, BDNF, IGF-1, or insulin signaling are implicated in the pathogenesis of Alzheimer disease. We have previously characterized a bigenic PS1؋APP transgenic mouse displaying early hippocampal A␤ deposition (3 to 4 months) but late (17 to 18 months) neurodegeneration of pyramidal cells, paralleled to the accumulation of soluble A␤ oligomers. We hypothesized that PI3K/Akt/GSK-3␤ signaling pathway could be involved in this apparent age-dependent neuroprotective/neurodegenerative status. In fact, our data demonstrated that, as compared with age-matched nontransgenic controls, the Ser-9 phosphorylation of GSK-3␤ was increased in the 6-month PS1؋APP hippocampus, whereas in aged PS1؋APP animals (18 months), GSK-3␤ phosphorylation levels displayed a marked decrease. Using N2a and primary neuronal cell cultures, we demonstrated that soluble amyloid precursor protein-␣ (sAPP␣), the predominant APP-derived fragment in young PS1؋APP mice, acting through IGF-1 and/or insulin receptors, activated the PI3K/Akt pathway, phosphorylated the GSK-3␤ activity, and in consequence, exerted a neuroprotective action. On the contrary, several oligomeric A␤ forms, present in the soluble fractions of aged PS1؋APP mice, inhibited the induced phosphorylation of Akt/GSK-3␤ and decreased the neuronal survival. Furthermore, synthetic A␤ oligomers blocked the effect mediated by different neurotrophins (NGF, BDNF, insulin, and IGF-1) and sAPP␣, displaying high selectivity for NGF. In conclusion, the age-dependent appearance of APP-derived soluble factors modulated the PI3K/Akt/GSK-3␤ signaling pathway through the major neurotrophin receptors. sAPP␣ stimulated and A␤ oligomers blocked the prosurvival signaling. Our data might provide insights into the selective vulnerability of specific neuronal groups in Alzheimer disease.The molecular mechanisms underlying the selective neurodegeneration in Alzheimer disease (AD) 5 remain unclear. Amyloid-␤ (A␤) peptides, proteolytically excised from the amyloid precursor protein (APP), are considered the primary pathological agents in AD. However, their precise modes of action, toxic conformational forms, and molecular targets are still controversial (for review see Ref. 1). Transgenic mouse models, overexpressing mutated forms of human APP, are widely used to study AD pathogenesis. These models develop extensive A␤ deposition in the disease-vulnerable brain regions (such as hippocampus); however, neurons are well protected until late ages. The factors and pathways maintaining neuronal integrity at young/middle ages in these AD models and those inducing neurodegeneration in the aged animals remains to be defined.NGF, BDNF, IGF-1, and insulin are trophic factors critical for neuronal survival and plasticity, underlying memory, and learning (2-4) and could be implicated in AD development.

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Inhibition of Wnt signaling, modulation of Tau phosphorylation and induction of neuronal cell death by DKK1

Cited by 116 publications

References 69 publications

The Secreted Wnt Antagonist Dickkopf-1 Is Required for Amyloid β-Mediated Synaptic Loss

The Secreted Wnt Antagonist Dickkopf-1 Is Required for Amyloid β-Mediated Synaptic Loss

Therapeutic Potential of Mood Stabilizers Lithium and Valproic Acid: Beyond Bipolar Disorder

Age-dependent Accumulation of Soluble Amyloid β (Aβ) Oligomers Reverses the Neuroprotective Effect of Soluble Amyloid Precursor Protein-α (sAPPα) by Modulating Phosphatidylinositol 3-Kinase (PI3K)/Akt-GSK-3β Pathway in Alzheimer Mouse Model

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