Peroxisome proliferator-activated receptor gamma is expressed in hippocampal neurons and its activation prevents beta-amyloid neurodegeneration: role of Wnt signaling.

The molecular pathogenesis of Alzheimer's disease (AD) involves the participation of the amyloid-beta-peptide (A beta), 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) PPAR gamma is present in rat hippocampal neurons in culture. (2) Activation of PPAR gamma by troglitazone and rosiglitazone protects rat hippocampal neurons against A beta-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 A beta-induced rise in bulk-free Ca2+. (4) PPAR gamma 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 PPAR gamma prevents A beta-induced neurodegeneration by a mechanism that may involve a cross talk between neuronal PPAR gamma and the Wnt signaling pathway. More important, the fact that the activation of PPAR gamma attenuated A beta-dependent neurodegeneration opens the possibility to fight AD from a new therapeutic perspective.