Apoptosis was linked to an inability of Tg2576 neurons to maintain K + homeostasis following acute treatment with extracellular Ab1-40. Chronic exposure to 1 mM Ab1-40 also caused the generation of hyperphosphorylated tau-immunoreactive axonal swellings in Tg2576 but not wildtype neurons. Our data suggest that chronic exposure to both intra- and extra-cellular Ab induces neurodegenerative changes that bear similarities to some of the pathological hallmarks of AD. AD is a progressive neurodegenerative disease, in which neurons are likely to be exposed to sublethal concentrations of both intracellular and extracellular Ab for extended periods of time. To experimentally model this situation, Tg2576 neurons and wildtype neurons received daily treatment with soluble, monomeric Ab for 6 days. While this chronic exposure to Ab did not kill wildtype neurons, it caused substantial apoptosis of Tg2576 neurons. Further studies revealed that Tg2576 neurons were unable to maintain K + and H + homeostasis following Ab treatment, leading to prolonged extrusion of potassium and influx of protons into Tg2576 neurons. Furthermore, chronic exposure to 1 mM Ab for six days caused the generation of hyperphosphorylated tau-immunoreactive axonal swellings in Tg2576 but not wildtype neurons. In summary, our data suggest that chronic exposure to sublethal levels of both intra- and extra-cellular Ab induces neurodegenerative changes in cultured neurons that bear similarities to pathological hallmarks observed in AD. These changes appear to be driven by an inability of Tg2576 to maintain normal K + homeostasis in Ro 04-6790 response to continual exposure to extracellular Ab. The mechanism by which Ab causes neurotoxicity or neuronal dysfunction remains to be fully resolved. Numerous studies have used cultured neurons to investigate the neurotoxic actions of Ab, and can generally be classified into two paradigms; experiments whereby Ab is applied acutely or chronically to cultured neurons, and experiments using neurons cultured from transgenic AD mice which express human Ab. The former experiments have been particularly informative, revealing important information regarding the concentration and Remacemide hydrochloride biochemical form of extracellular Ab that exhibits toxicity upon cultured neurons; from such studies it is proposed that soluble oligomeric forms of Ab at.5 mM concentrations are the most toxic form of extracellular Ab to neurons.