The neurotoxic effects of soluble and aggregated synthetic amyloid beta protein (A beta P) have been investigated in rat primary cultures. Freshly solubilized beta(1-40) was neurotoxic not to immature, but to mature hippocampal neurons. On the other hand, aggregated beta(1-40) was neurotoxic to both. Neurotoxicity induced by aggregated beta(1-40) was 10-fold more potent than soluble beta(1-40) and was not prevented by substance P. The neurotoxicity of aggregated beta(1-40) to cultured neurons depended on the peptide concentration and the duration of exposure to it. Cerebral cortical and hippocampal neurons were significantly susceptible to aggregated beta(1-40) than cerebellar granular cells, and cultured astrocytes were not vulnerable to aggregated beta(1-40) even at high concentrations.