Alzheimer’s disease is a neurodegenerative disorder the incidence of which is increased following ischaemic/hypoxic episodes such as stroke (Desmond et al, 2002). Inherited forms of the disorder often involve mutations in the endoplasmic reticulum-associated protein presenilin-1 (PS-1). In this study we have investigated the effects of PS-1 and an Alzheimer’s disease related mutation to PS-1 on survival of a neuronal cell line following an ischaemic/hypoxic challenge. Untransfected SH-SY5Y cells and SH-SY5Y cells stably transfected to overexpress either wild type PS-1 (PS-1wt) (≥10-fold) or an Alzheimer’s disease related deletion mutation (ΔE9) of PS-1 were grown and prepared as described in Plant et al (2002). To mimic ischaemia cells were subjected to increasing concentrations of 2-deoxy-D-glucose (2-DG) and/or hypoxia (2.5% O₂) for 48 hours. In some cells the effects of serum omission from the culture media were also investigated. Cell viability was measured using the 3-(4,5-dimethylthiazol-2-yl)-w, 5-diphenyltetrazolium bromide (MTT) assay as described previously (Plant et al 2003). Values given are means±s.e.m. (n=6) and statistical significance was assessed using Student’s paired or unpaired t test as appropriate. Removal of serum from the culture medium reduced the viability of untransfected SH-SY5Y to 80±7% of controls (P<0.02). In PS-1wt and ΔE9 viability was reduced to 67±6% (P<0.01) and 71±5% (P<0.01) respectively. Hypoxia alone had no effect on the viability of any of the cell lines although 2-DG caused a concentration-dependent decrease in cell viability to 54±7% of control (untransfected cells), 44±5% (PS-1) and 40±4% (ΔE9) at a concentration of 20mM. When untransfected cells were simultaneously challenged with 2-DG and hypoxia, no additive effect could be seen (63±12%). This was also the case in ΔE9 cells (56±6%). Interestingly, in cells overexpressing PS-1 hypoxia reversed the effect of 20mM 2-DG (97±10%) and also reversed the effect of serum omission. The detrimental effect of removing serum from the culture medium was additive with that of 2-DG in all cell lines. These data show that neither the PS-1 nor the ΔE9 overexpressing cells show an altered sensitivity to either 2-DG or serum deprivation toxicity. However, in PS-1 overexpressing cells hypoxia was able to reverse the deleterious effects of both 2-DG and serum deprivation. This was not seen in the ΔE9 cells, suggesting that a protective effect of PS-1 may be lost by an Alzheimer's disease-related mutation.