Browsing by Author "Godoy, JA"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Peroxisome proliferator-activated receptor gamma is expressed in hippocampal neurons and its activation prevents beta-amyloid neurodegeneration: role of Wnt signaling
    (ELSEVIER INC, 2005) Inestrosa, NC; Godoy, JA; Quintanilla, RA; Koenig, CS; Bronfman, M
    The molecular pathogenesis of Alzheimer's disease (AD) involves the participation of the amyloid-beta-peptide (Abeta), which plays a critical role in the neurodegeneration that triggers the disease. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors, which are members of the nuclear receptor family. We report here that (1) PPARgamma is present in rat hippocampal neurons in culture. (2) Activation of PPAR-gamma by troglitazone and rosiglitazone protects rat hippocampal neurons against Abeta-induced neurodegeneration, as shown by the 3-[4,5 -2yl]-2,5-diphenyltetrazolium bromide (MTT) reduction assay, immunofluorescence using an anti-heavy neurofilament antibody, and quantitative electron microscopy. (3) Hippocampal neurons treated with several PPAR-gamma agonists, including troglitazone, rosiglitazone, and ciglitazone, prevent the excitotoxic Abeta-induced rise in bulk-free Ca2+. (4) PPARgamma activation results in the modulation of Wnt signaling components, including the inhibition of glycogen synthase kinase-3beta (GSK-3beta) and an increase of the cytoplasmic and nuclear beta-catenin levels. We conclude that the activation of PPARgamma prevents Abeta-induced neurodegeneration by a mechanism that may involve a cross talk between neuronal PPAR-y and the Writ signaling pathway. More important, the fact that the activation of PPAR-y attenuated Abeta-dependent neurodegeneration opens the possibility to fight AD from a new therapeutic perspective. (C) 2004 Published by Elsevier Inc.
  • No Thumbnail Available
    Item
    The anti-inflammatory and cholinesterase inhibitor bifunctional compound IBU-PO protects from β-amyloid neurotoxicity by acting on Wnt signaling components
    (2005) Farías, GG; Godoy, JA; Vázquez, MC; Adani, R; Meshulam, H; Avila, J; Amitai, G; Inestrosa, NC
    Changes in signal transduction are implicated in neuronal responses to the Alzheimer's amyloid-beta-peptide (A), 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 Abeta-neurotoxicity, and its activity is associated to Wnt signaling components in rat hippocampal and mouse cortical neurons. IBU-PO (0.01-1 muM) inhibits glycogen-synthase-kinase-3 (GSK-3beta) and stabilizes cytoplasmic beta-catenin reverting the silencing of the Wnt pathway caused by Abeta-toxicity and GSK-3beta overexpression. In addition, IBU-PO enhances, dose-dependently, the non-amyloidogenic amyloid precursor protein (APP) cleavage by increasing secreted APP and decreasing endogenous Abeta(1-40) in rat hippocampal neurons. (C) 2004 Elsevier Inc. All rights reserved.