The amyloid β-peptide (Aβ) is produced by proteolytic processing of the amyloid precursor protein and it has been suggested, both on genetic grounds and on experimental evidence, that Aβ is central to the pathogenesis of Alzheimer’s disease. Controversy remains regarding the primary pathogenic structure of Aβ, the cell type it targets and the molecular events underlying its toxicity. While the original formulation of the amyloid hypothesis implicates fibrils in neurodegeneration, more recent evidence suggests that soluble oligomers are the primary neurotoxic agents. Studies have shown that soluble oligomers, but not momomers or fibrils, elicit rapid Ca2+ signals in SH-SY5Y cells 1. Aβ has also been reported to elicit Ca2+ responses and the generation of reactive oxygen species in astrocytes, though cell death was confined to neurons due to a suggested lack of antioxidant support 2. We aim to identify the primary pathogenic structure of Aβ, its primary cellular target and its pathological mechanism. Initial experiments will be conducted in the SH-SY5Y neuroblastoma cell line and ultimately in primary hippocampal cultures. After in vitro incubation, we have shown a time-dependent increase in the mass of the Aβ oligomeric species. Exposure of cells to Aβ42 for 48hr induced death in 50% of cells as determined by the release of lactate dehydrogenase. Furthermore, a MTT assay measured that 30% of cells remained viable following a 24hr exposure to Aβ42. To determine whether dysregulation of intracellular Ca2+ homeostasis contributed to the toxic effects of Aβ42, we investigated whether exposure of cells to peptide induced elevations in intracellular [Ca2+]: Fura-2 loaded SH-SY5Y cells were imaged for a 30min period following exposure to Aβ42 that had been pre-aggregated (1hr, 2hr or 24hr). A saturating dose of carbachol (100µM) was applied thereafter to demonstrate cell viability and that the Ca2+ stores were intact. Application of peptide that had been pre-aggregated for 1hr or 2hr induced Ca2+ transients in less than 2% of cells. Peptide that had been pre-aggregated for 24hr induced Ca2+ transients in a greater number of cells (<5 %). The amplitude of the carbachol-induced Ca2+ transient was unaffected by Aβ42 application, irrespective of the pre-aggregation time. The Ca2+ responses recorded exhibited no trend in their time of onset, frequency, amplitude or duration, suggesting a non-regulated process. A large degree of variability was observed both within and between experiments. No Ca2+ responses were recorded in any of the control experiments. In summary, we have shown that Aβ42 induces cell death and Ca2+ increase in SH-SY5Y cells.