The anti-inflammatory and cholinesterase inhibitor bifunctional compound IBU-PO protects from β-amyloid neurotoxicity by acting on Wnt signaling components

Changes in signal transduction are implicated in neuronal responses to the Alzheimer's amyloid-β-peptide (Aβ), which include neurotransmitter systems and pathways involved in the maintenance of the nervous system. We report here that a new bifunctional compound IBU-PO, which combines a non-steroidal anti-inflammatory drug (NSAID) (Ibuprofen) and a cholinesterase (ChE) inhibitor (Octyl-Pyridostigmine), is neuroprotective against Aβ-neurotoxicity, and its activity is associated to Wnt signaling components in rat hippocampal and mouse cortical neurons. IBU-PO (0.01-1 μM) inhibits glycogen-synthase-kinase-3β (GSK-3β) and stabilizes cytoplasmic β-catenin reverting the silencing of the Wnt pathway caused by Aβ-toxicity and GSK-3β overexpression. In addition, IBU-PO enhances, dose-dependently, the non-amyloidogenic amyloid precursor protein (APP) cleavage by increasing secreted APP and decreasing endogenous Aβ1-40 in rat hippocampal neurons.