Hypoxia has been shown to increase amyloid precursor protein processing (Plant et al, 2003) a key element of which is the protein presenilin-1 (PS-1). In this study we have investigated the role of PS-1 on survival of a neuronal cell line following acute anoxic and hypoglycaemic challenges. Untransfected SH-SY5Y cells, SH-SY5Y cells stably transfected to over-express either wild type PS-1 (PS-1wt) or an exon 9 deletion mutation (ΔE9) of PS-1 and primary cultures of neurones isolated from cortex of humanely killed rats were grown and prepared as described (Plant et al, 2002, 2003). To mimic ischaemia cells were exposed to media containing 25mM 2-deoxy-D-glucose (hypoglycaemia) and/or grown in a chamber suffused with 5% CO₂/95% N₂ (ischaemia) for 3h. Cell viability was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoium bromide (MTT) assay as described previously (Plant et al, 2003). Values given are means±s.e.m. and statistical significance was assessed using Student’s paired or unpaired t-test as appropriate. In untransfected SH-SY5Y cells 3h ischaemia significantly reduced cell viability to 74±2% (n=70 triplicate measurements from 5 batches of cells, p<0.05). In the same cell line hypoglycaemia reduced viability to 77±1%. In these cells the effects of ischaemia and hypoglycaemia were additive, reducing cell viability to 51±2%. Ischaemia produced a small reduction in the viability of ΔE9 cells to 95±2% (p<0.01, n=70, 5). Exposing ΔE9 cells to hypoglycaemia produced a larger decrease viability to 62±3% (P<0.05) compared to untransfected SH-SY5Y. Surprisingly ischaemia had no effect on the viability of PS-1wt cells (98±2%, n=126, 7) although hypoglycaemia was able to reduce PS-1wt viability to a similar degree to that in untransfected cells (80±1%, p<0.01). Cortical neurones were susceptible to hypoglycaemia with viability reduced to 91±4% (p<0.05, n=14) and vulnerable to ischaemia (83±2% viability, p<0.001). In these cultures the effects of ischaemia and hypoglycaemia were additive, reducing cell viability to 75±3%. These data suggest that over-expression of PS-1 in SH-SY5Y cells has a protective effect against cell death induced by acute ischaemia but not against the effects of glucose deprivation. It is unclear whether this is an effect specific to PS-1 or is simply due to increased protein expression since only minimal cell death was seen in the ΔE9 cells. Effects of ischaemia and hypoglycaemia on the untransfected SH-SY5Y cell line were qualitatively similar to those seen in primary neuronal cultures.