The role played by the β-amyloid protein in the neuropathology which accompanies Alzheimer's disease remains unclear. In an effort to unravel some of the cellular actions of β-amyloid, we investigated its effects on nitric oxide (NO) release in cultured neuron. The putative neurotoxic fragment 25–35 of β-amyloid stimulated release of NO in a neuronal cell line, as measured by an increase in cyclic GMP formation which is attenuated by NO synthase inhibitors and NO scavengers. These results suggest that NO might mediate intercellular communication effected by β-amyloid. Our results provide the first piece of evidence that β-amyloid directly activates a putative neurotoxic second messenger transduction mechanism. These findings might be of potential value in understanding the molecular basis of Alzheimer's disease pathology and in targeting new effective therapeutic approaches.