ALZHEIMER'S disease is the most common cause of progressive intellectual failure¹. The lesions that develop, called senile plaques, are extracellular deposits principally composed of insoluble aggregates of β-amyloid protein (Aβ), infiltrated by reactive microglia and astrocytes^2,3. Although Aβ, and a portion of it, the fragment 25–35 (Aβ(25–35)), have been shown to exert a direct toxic effect on neurons^4–6, the role of microglia in such neuronal injury remains unclear⁷. Here we report a synergistic effect between Aβ and interferon-γ (IFN-γ) in triggering the production of reactive nitrogen intermediates and tumour-necrosis factor-α (TNF-α) from microglia. Furthermore, using co-culture experiments, we show that activation of microglia with IFN-γ and Aβ leads to neuronal cell injury in vitro. These findings suggest that Aβ and IFN-γ activate microglia to produce reactive nitrogen intermediates and TNF-α, and this may have a role in the pathogenesis of neuronal degeneration observed in ageing and Alzheimer's disease.