The Wnt pathway, cell-cycle activation and β-amyloid: novel therapeutic strategies in Alzheimer's disease?

Caricasole, Andrea; Copani, Agata; Caruso, Alessandra; Caraci, Filippo; Iacovelli, Luisa; Sortino, Maria Angela; Terstappen, Georg C.; Nicoletti, Ferdinando

doi:10.1016/s0165-6147(03)00100-7

Cited by 125 publications

(103 citation statements)

References 48 publications

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“…Dickkopf-1 and focal brain ischemiaingly, the dkk-1 gene is a transcriptional target for p53, and increases in p53 levels drive the expression of Dkk-1 in cultured neurons challenged with bamyloid (Caricasole et al, 2003). A possible scenario is that DNA damage increases the expression of p53 in neurons of the ischemic penumbra, and p53 in turn drives the induction of Dkk-1 and the resulting inhibition of the canonical Wnt pathway.…”

Section: Discussionmentioning

confidence: 99%

“…A growing body of evidence shows that inhibition of the canonical Wnt pathway contributes to the pathophysiology of neuronal damage in model of acute and chronic neurodegenerative disorders (De Ferrari and Inestrosa, 2000;Garrido et al, 2002;Inestrosa et al, 2002;Caricasole et al, 2003Caricasole et al, , 2004De Ferrari et al, 2003;Cappuccio et al, 2005;Scali et al, 2006;Busceti et al, 2007). Wnts are members of a family of secreted glycoproteins that regulate neuronal homeostasis during development, as well as in the adult life (Dale, 1998).…”

Section: Introductionmentioning

confidence: 99%

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Induction of the Wnt Antagonist, Dickkopf-1, Contributes to the Development of Neuronal Death in Models of Brain Focal Ischemia

Mastroiacovo

Busceti

Biagioni

et al. 2008

J Cereb Blood Flow Metab

Self Cite

107

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Inhibition of the canonical Wnt pathway has been implicated in the pathophysiology of neuronal death. Here, we report that the secreted Wnt antagonist, Dickkopf-1 (Dkk-1) is rapidly induced in neurons after induction of focal brain ischemia. In rats undergoing transient focal ischemia in response to brain infusion of endothelin-1, Dkk-1 was induced in neurons of the ischemic core and the penumbra region. Induction of Dkk-1 was associated with a reduced expression of b-catenin (a downstream signaling molecule of the canonical Wnt pathway), and was not observed in neurons expressing the protective protein, heat shock protein-70. Treatment with lithium ions, which, inter alia, rescue the canonical Wnt pathway, was highly protective against ischemic damage. Dkk-1 was also induced in cortical neurons of mice undergoing permanent middle cerebral artery (MCA) occlusion. This model allowed us to compare wild-type mice with doubleridge mice, which are characterized by a reduced expression of Dkk-1. Doubleridge mice showed an attenuated reduction of b-catenin and a reduced infarct volume in response to MCA occlusion, providing a direct demonstration that Dkk-1 contributes to the pathophysiology of ischemic neuronal damage. These data rise the interesting possibility that Dkk-1 antagonists or drugs that rescue the Wnt pathway might be neuroprotective in stroke.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Induction of the Wnt Antagonist, Dickkopf-1, Contributes to the Development of Neuronal Death in Models of Brain Focal Ischemia

Mastroiacovo

Busceti

Biagioni

et al. 2008

J Cereb Blood Flow Metab

Self Cite

107

View full text Add to dashboard Cite

show abstract

“…However, it should be noted that conditional double knockout of both PS-1 and PS-2 in mice has been shown to decrease CBP expression (41). Aberrant Wnt signaling has previously been speculated to play a part in AD neuronal degeneration (42)(43)(44); however, the complexity of this signaling pathway (45) has complicated the analysis. We propose that the selective increase of a subset of TCF͞␤-catenin-dependent transcription is associated with defective exit from the cell cycle and NGF-induced neuritogenesis seen in the PC-12͞L286V cells.…”

Section: Discussionmentioning

confidence: 99%

Specific inhibition of CBP/β-catenin interaction rescues defects in neuronal differentiation caused by a presenilin-1 mutation

Teo

Nguyen

et al. 2005

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

152

133

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mutant, PS-1(L286V), causes a dramatic increase in T cell factor (TCF)͞␤-catenin transcription in PC-12 cells, which prevents normal nerve growth factor (NGF)-induced neuronal differentiation and neurite outgrowth. Selective inhibition of TCF͞␤-catenin͞cAMP-response elementbinding protein (CREB)-binding protein (CBP)-mediated transcrip-tion, but not TCF͞␤-catenin͞p300, with the recently described small molecule antagonist ICG-001 corrects these defects in neuronal differentiation, highlighting the importance of Wnt͞␤-catenin signaling in this process. We propose that increased TCF͞␤-catenin͞ CBP-mediated transcription, as well as a failure to switch to TCF͞␤-catenin͞p300-mediated transcription, play an important role in decreasing neuronal differentiation.Wnt͞␤-catenin ͉ Alzheimer's disease

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“…Remarkably, it has been reported that Ab neurotoxicity induces the expression of Dickkopf 1 (Dkk1) (Caricasole et al, 2004), which may further antagonize Wnt presentation to its complex receptor. All together the data indicate that the activity of Wnt signaling components is compromised in AD brains and thus underlies Ab generation/toxicity/deposition and tau hyperphosphorylation, major pathological hallmarks of this neurodegenerative condition (De Ferrari and Inestrosa, 2000;Mudher and Lovestone, 2002;Caricasole et al, 2003;Moon et al, 2004).…”

Section: Alzheimer's Disease Apolipoprotein E and Wnt Signalingmentioning

confidence: 96%

The ups and downs of Wnt signaling in prevalent neurological disorders

2006

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In order to function properly, the brain must be wired correctly during critical periods in early development. Mistakes in this process are hypothesized to occur in disorders like autism and schizophrenia. Later in life, signaling pathways are essential in maintaining proper communication between neuronal and non-neuronal cells, and disrupting this balance may result in disorders like Alzheimer's disease. The Wnt/b-catenin pathway has a well-established role in cancer. Here, we review recent evidence showing the involvement of Wnt/b-catenin signaling in neurodevelopment as well as in neurodegenerative diseases. We suggest that the onset/development of such pathological conditions may involve the additive effect of genetic variation within Wnt signaling components and of molecules that modulate the activity of this signaling cascade.

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The Wnt pathway, cell-cycle activation and β-amyloid: novel therapeutic strategies in Alzheimer's disease?

Cited by 125 publications

References 48 publications

Induction of the Wnt Antagonist, Dickkopf-1, Contributes to the Development of Neuronal Death in Models of Brain Focal Ischemia

Induction of the Wnt Antagonist, Dickkopf-1, Contributes to the Development of Neuronal Death in Models of Brain Focal Ischemia

Specific inhibition of CBP/β-catenin interaction rescues defects in neuronal differentiation caused by a presenilin-1 mutation

The ups and downs of Wnt signaling in prevalent neurological disorders

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