The role of beta-amyloid in Alzheimer's disease and its cellular mechanism of action are still unclear. Based on observations that beta-amyloid influences neuronal calcium homeostasis we investigated the effect of the peptide on K(+)-induced enhancement of free intracellular calcium in dissociated neurons from adult mice. Preincubation with beta-amyloid fragment 25-35 at concentrations > or = 0.05 mumol/l resulted in marked amplification of the K(+)-induced Ca2+ response. This effect was also observed with fragment 1-40, whereas fragment 1-28 or 12-28 did not affect the Ca2+ response. This preparation therefore presents a valuable model to investigate the action of beta-amyloid ex vivo in individual animals. Our findings suggest a small but consisting destabilizating effect of beta-amyloid on neuronal Ca2+ homeostasis resulting in chronically increased neuronal vulnerability.