Previous studies have shown that okadaic acid (OA) evokes tau phosphorylation and neurofibrillary changes in vivo, and in cultured neurons, that resemble Alzheimer's disease pathogenesis. In order to investigate the mechanism of OA-neurotoxicity, we treated cultured rat neurons with OA and examined nuclear morphology, phosphatidylserine (PS) externalization, alpha-fodrin cleavage, and the effects of cell death inhibitors. Our results demonstrated that cycloheximide (CHX) and the broad-spectrum caspase inhibitor, ZVAD, significantly reduced cell death in a dose-dependent manner. Nuclear fragmentation, a hallmark of apoptosis, occurred after OA treatment and was inhibited by CHX or ZVAD. PS externalization was apparent in 6-12 h in neurites and in cell bodies, and peaked at 24 h after OA treatment. Cleavage of alpha-fodrin as visualized by the appearance of 150- and 120-kDa bands appeared with a time course similar to PS externalization. These results suggest that OA induce CHX and caspase sensitive neuronal apoptosis.