The best established risk factor for Alzheimer’s disease is age, which is intimately involved with oxidative stress. The induction of endoplasmic reticulum (ER) stress was recently reported to be involved in Alzheimer’s disease (AD). In addition, presenilin-1 (PS1) mutations have been associated with vulnerability to ER stress. Studies in model neuronal-origin cells suffering ER and oxidative stress, mimicking the situation in AD brains, are therefore of great interest. This thesis reports that, in the SK-N-MC human neuroblastoma cell line, ER-specifi c stress produced by tunicamycin in the presence of oxidative stress produced by the xanthine/xanthine oxidase system leads to increased cell injury, higher cytosolic calcium concentrations, and a greater production of reactive oxygen species (ROS). Further, ER stress in the presence of oxidative stress enhances the Integrated Stress Response (ISR), such the survival machinery (unfolded protein response, UPR) as the cell death. ER stress in the presence of oxidative stress enhances CHOP expression (a marker of cell death caused by ER stress) and leads to increased apoptosis induced by the increased release of mitochondrial cytochrome c to the cytosol, the activation of caspase 3, and the degradation of poly (ADP-ribose) polymerase (PARP). This increase in apoptosis was confi rmed by quantifying DNA fragmentation using fl ow cytometry. cDNA Microarrays were used to identify genes with changes in the expression in response to ER stress in the presence of oxidative stress. In this thesis, we suggest a neuronal model of induction of ER stress in concert with oxidative stress to study the molecular mechanisms of AD-associated neurodegeneration.

El presente trabajo ha sido realizado en el Departamento de Biología Molecular del Centro de Biología Molecular “Severo Ochoa” de la Facultad de Ciencias de la Universidad Autónoma de Madrid, gracias a un beca fi nanciada por la Fundación Ramón Areces.

Tesis doctoral inédita de la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología molecular. Fecha de lectura: 16-02-2007

Peer reviewed