Elevated levels of the amyloid beta (Aβ) peptide is one of the key pathological hallmarks of Alzheimer’s disease (1). The Aβ peptide is produced by the sequential cleavage of two proteases known as β and γ secretase. Aβ₄₀ has previously been found at nM concentrations in the cerebrospinal fluid of healthy individuals (2) however, at present a physiological role for the Aβ peptide remains elusive. The aim of the study was to determine the effects of inhibiting the β and γ secretase enzymes initially using commercially available secretase inhibitors and subsequently by shiRNA of the BACE 1 gene to investigate a potential physiological role for the Aβ peptide. Human SH-SY5Y neuroblastoma cells were treated with 10μM of the respective γ secretase inhibitors γI, γIV or γVI for 24 hrs, and the cell viability and caspase 3/7 activity were determined using MTT and caspase 3/7 assays respectively. Small interfering RNA (shiRNA) duplexes were designed against BACE-1. BACE 1 shiRNA was transfected into SH-SY5Y neuroblastoma cells using the GFP-tagged plentilox 3.7 virus. Reaggregate cultures of cerebellar granule neurones (CGN) were prepared and treated with either 10μM of the γ secretase inhibitors γI, γIV or γVI for 24 hrs. CGNs were fixed in 3.5 % paraformaldehyde and the neurites were immunocytochemically stained using the MAP2 neuronal marker. The neurite length from each reaggregate culture was measured using Image J software. Results are expressed as mean ± SEM. Statistical significance was assigned using One-Way ANOVA. There was a significant reduction in cell viability and a corresponding increase in caspase 3/7 activity following treatment with γI a selective inhibitor of Aβ_1-40 (44.35 ± 3.01 % of control for cell viability) (353.4 ± 8.53 % of control for caspase 3/7), and γIV, an inhibitor of both the Aβ_1-40 and Aβ₄₂ peptides (54.05 ± 8.76 % of control for cell viability) (218.4±13.11 % of control for caspase 3/7). γVI, the selective Aβ₄₂ inhibitor had no effect on cell viability (102 ± 8.67 % of control) or caspase 3/7 activity (118.78 ± 28.04 % of control) (n=4). When the BACE 1 gene was silenced in SH-SY5Y neuroblastoma cells, this produced a decrease in cell viability (0.011± 0.001 AU/mg protein) compared to the control cells (0.020±0.002 AU/mg protein) and a corresponding increase in caspase 3/7 activity (n=4). Treatment with either 10μM γI or γIV significantly reduced neurite outgrowth in cerebellar granule reaggregate cultures (n=3). However treatment with the γVI secretase inhibitor had no effect on neurite outgrowth (n=3). The study provides evidence that the Aβ_1-40 peptide is important in neurite outgrowth and additionally in the regulation of cell survival.