Although considerable research has shown a role for peroxisome proliferator-activated receptors (PPAR) in adipose differentiation and in the regulation of inflammation, little is known about its possible functions in neurons. We investigated the role of PPARγ in primary cultures of cortical neurons and human neuroblastoma SH-SY5Y cells. Incubation of cortical neurons with the specific PPARγ ligand 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) induced morphological changes including neurite degeneration and nuclear condensation that were consistent with neurons dying by apoptosis. The morphological changes associated with incubation of cortical neurons with 15d-PGJ2 were prevented following pretreatment of neurons with the general caspase inhibitor, Z-VAD. These results highlight a novel role for PPARγ in neurons and suggest that unwarranted activation of PPARγ may contribute to the neuronal apoptosis associated with certain neurodegenerative disorders including Alzheimer's disease (AD).