Synaptotoxicity in Alzheimer's disease: The Wnt signaling pathway as a molecular target

Nibaldo C. Inestrosa, Lorena Varela-Nallar, Catalina P. Grabowski, Marcela Colombres

Research output: Contribution to journalArticlepeer-review

60 Citations (Scopus)


Recent evidence supports a role of the Wnt pathway in neurodegenerative disorders such as Alzheimer's disease (AD). A relationship between amyloid-β-peptide (Aβ)-induced neurotoxicity and a decrease in the cytoplasmatic levels of β-catenin has been proposed. Also, the inhibition of glycogen synthase kinase (GSK-3β), a central modulator of the pathway, protects rat hippocampal neurons from Aβ-induced damage. Interestingly, during the progression of AD, it has been described that active GSK-3β is found in neuronal cell bodies and neurites, co-localizing with pre-neurofibrillary tangles observed in disease brains. Since Aβ oligomers are associated with the post-synaptic region and we have found that the non-canonical Wnt signaling modulates PSD-95 and glutamate receptors, we propose that the synaptic target for Aβ oligomers in AD is the postsynaptic region and at the molecular level is the non-canonical Wnt signaling pathway. Altogether, our evidence suggests that a sustained loss of Wnt signaling function may be involved in the Aβ-dependent neurodegeneration observed in AD brains and that the activation of this signaling pathway could be of therapeutic interest in AD.

Original languageEnglish
Pages (from-to)316-321
Number of pages6
JournalIUBMB Life
Issue number4-5
Publication statusPublished - 2007


  • Alzheimer's disease
  • GSK-3β
  • Neurodegeneration
  • Wnt signaling
  • β-catenin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics
  • Clinical Biochemistry
  • Cell Biology


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