Cellular consequences of the expression of Alzheimer's disease-causing presenilin 1 mutations in human neuroblastoma (SH-SY5Y) cells

Abstract Mutations in the presenilin 1 (PS1) gene lead to early-onset Alzheimer's disease with the S170F mutation causing the earliest reported age of onset. Expression of this, and other PS1 mutations, in SH-SY5Y cells resulted in significant loss of cellular viability compared to control cells. Basal Ca 2 + concentrations in PS1 mutants were never lower than controls and prolonged incubation in Ca 2 + -free solutions did not deplete Ca 2 + stores, demonstrating there was no difference in Ca 2 + leak from endoplasmic reticulum (ER) stores in PS1 mutants. Peak muscarine-evoked rises of [Ca 2 + ]i were variable, but the integrals were not significantly different, suggesting, while kinetics of Ca 2 + store release might be affected in PS1 mutants, store size was similar. However, when Ca 2 + -ATPase activity was irreversibly inhibited with thapsigargin, the S170F and ΔE9 cells showed larger capacitative calcium entry indicating a direct effect on Ca 2 + influx pathways. There was no significant effect of any of the mutations on mitochondrial respiration. Amyloid β(Aβ(1–40)) secretion was reduced, and Aβ(1–42) secretion increased in the S170F cells resulting in a very large increase in the Aβ42/40 ratio. This, rather than any potential disruption of ER Ca 2 + stores, is likely to explain the extreme pathology of this mutant.