Boyle 2012 Brain Res

Boyle JP, Hettiarachchi NT, Wilkinson JA, Pearson HA, Scragg JL, Lendon C, Al-Owais MM, Kim CB, Myers DM, Warburton P, Peers C (2012) Cellular consequences of the expression of Alzheimer's disease-causing presenilin 1 mutations in human neuroblastoma (SH-SY5Y) cells. Brain Res 1443:75-88.

» PMID: 22297172

Boyle JP, Hettiarachchi NT, Wilkinson JA, Pearson HA, Scragg JL, Lendon C, Al-Owais MM, Kim CB, Myers DM, Warburton P, Peers C (2012) Brain Res

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 Ca²⁺ concentrations in PS1 mutants were never lower than controls and prolonged incubation in Ca²⁺-free solutions did not deplete Ca²⁺ stores, demonstrating there was no difference in Ca²⁺ leak from endoplasmic reticulum (ER) stores in PS1 mutants. Peak muscarine-evoked rises of [Ca²⁺](i) were variable, but the integrals were not significantly different, suggesting, while kinetics of Ca²⁺ store release might be affected in PS1 mutants, store size was similar. However, when Ca²⁺-ATPase activity was irreversibly inhibited with thapsigargin, the S170F and ΔE9 cells showed larger capacitative calcium entry indicating a direct effect on Ca²⁺ 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 Ca²⁺ stores, is likely to explain the extreme pathology of this mutant. • Keywords: Alzheimer's disease, Presenilin 1 (PS1), Amyloid β Aβ(1-40) and Aβ(1-42), Endoplasmic reticulum

• O2k-Network Lab: UK Leeds Peers C

Labels: MiParea: Respiration, nDNA;cell genetics, mt-Medicine  Pathology: Aging;senescence, Alzheimer's, Neurodegenerative 

Organism: Human  Tissue;cell: Neuroblastoma  Preparation: Intact cells 

Regulation: Calcium  Coupling state: ROUTINE 

HRR: Oxygraph-2k