Peroxisome proliferator-activated receptor gamma (PPARhas been proposed as a therapeutic target for neurodegenerative diseases because of its anti-inflammatory action in glial cells. However, PPARagonists prevent -amyloid (A)-induced neurodegeneration in hippocampal neurons and PPARis activated by the nerve growth factor (NGF) survival pathway, suggesting a neuroprotective anti-inflammatory independent action. Here we show that the PPAR agonist rosiglitazone (RGZ) protects hippocampal and dorsal root ganglion neurons against A-induced mitochondrial damage and NGF deprivation-induced apoptosis, respectively, and promotes PC12 cell survival. In neurons and in PC12 cells RGZ protective effects are associated with increased expression of the Bcl-2 anti-apoptotic protein. NGF-differentiated PC12 neuronal cells constitutively overexpressing PPARare resistant to A-induced apoptosis and morphological changes, and show functionally intact mitochondria and no increase in reactive oxygen species when challenged with up to 50 M H2O2. Conversely, cells expressing a dominant negative mutant of PPAR show increased A-induced apoptosis and disruption of neuronal-like morphology, and are highly sensitive to oxidative stress-induced impairment of mitochondrial function. Cells overexpressing PPARpresent a 4-5 fold increase in Bcl-2 protein content; whereas, in PPAR dominant negative expressing cells, Bcl-2 is barely detected. Bcl-2 knock down by siRNA in cells overexpressing PPAR results in increased sensitivity to A and oxidative stress, further suggesting that Bcl-2 up-regulation mediates PPAR protective effects. PPAR prosurvival action is independent of the signal-regulated MAP kinase or the Akt prosurvival pathways. Altogether, these data suggest that PPAR supports survival in neurons in part through a mechanism involving increased expression of Bcl-2.