Abstract
Recent evidence supports a neuroprotective role for Wnt signaling in neurodegenerative disorders such as Alzheimer's Disease (AD). In fact, a relationship between amyloid-β-peptide (Aβ)-induced neurotoxicity and a decrease in the cytoplasmic levels of β-catenin has been observed. Apparently Aβ binds to the extracellular cysteine-rich domain of the Frizzled receptor (Fz) inhibiting Wnt/β-catenin signaling. Cross-talk with other signaling cascades that regulate Wnt/β-catenin signaling, including the activation of M1 muscarinic receptor and PKC, the use of Ibuprofen-ChE bi-functional compounds, PPAR α, γ agonists, nicotine and some antioxidants, results in neuroprotection against Aβ. These studies indicate that a sustained loss of Wnt signaling function may be involved in the Aβ-dependent neurodegeneration observed in Alzheimer's brain. In conclusion the activation of the Wnt signaling pathway could be proposed as a therapeutic target for the treatment of AD.
Highlights
Alzheimer's disease (AD) is a neurodegenerative disorder associated with aging and characterized by fibrillar deposits of Aβ in subcortical brain regions
In the mammalian central nervous system (CNS), Wnt signal transduction is involved in neural induction and patterning in early embryogenesis; previous studies have linked Wnt signaling to neurodegenerative disorders such as AD [4,5,6]
As discussed by Baranski et al (2000) [64] it is possible that secreted frizzled-related protein (sFRP) operate agonistically to Wnt signaling in some circumstances: for example, sFRP2 (SARP-1) increases resistance of MCF7 breast adeno-carcinoma cells to apoptotic signals, whereas sFRP1 (SARP-2) sensitizes the same cell [63] via opposing effects on intracellular β-catenin levels. These results suggest that intercellular signals via the Wnt pathways are substantially disrupted in the degenerative state, and that targeting of sFRPs to key areas of the neuroretina may mediate mechanisms promoting or antagonizing cell death, similar mechanisms may be true for neurodegenerative diseases such as AD
Summary
Alzheimer's disease (AD) is a neurodegenerative disorder associated with aging and characterized by fibrillar deposits of Aβ in subcortical brain regions. The exposure of rat hippocampal neurons to Aβ result in three hallmarks related with Wnt signaling: (a) destabilization of endogenous levels of β-catenin, (b) an increase in GSK-3β activity and (c) a decrease in Wnt target gene transcription. Transgenic mice that over-express GSK-3β show low levels of Ser-9 phosphorylation and the IBU-PO treatment induces an increase in this phosphorylation [105] Compounds such as IBU-PO, which mimic the activation of the Wnt signaling pathway, could eventually rescue neurons from cytotoxicity through GSK-3β inhibition, which may be of potential benefit for the treatment of AD patients. Such drugs increase β-catenin content in hippocampal neurons, suggesting an interaction with the Wnt signaling pathway [109] Another PPAR, known as the PPARγ, plays an important role in the regulation of lipid metabolism [110]. The crosstalk of the Wnt signaling pathway with other cellular pathways is opening new possibilities for therapy
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