Copper overload triggers antioxidant defenses imbalance in hippocampal HT22 neurons

IGLESIAS GONZÁLEZ, PABLO; URANGA, ROMINA MARÍA; SALVADOR, GABRIELA ALEJANDRA

Mar del plata

Congreso; LI Reunión Anual de la Sociedad Argentina de Investigación en Bioquímica y Biología Molecular (SAIB); 2015

Sociedad Argentina de Investigación en Bioquímica y Biología Molecular (SAIB)

Copper (Cu)-induced oxidative stress has been involved in the pathogenesis of several neurodegenerative diseases such as Alzheimer?s disease and related disorders. In this work, we characterized the response of hippocampal neurons to Cu overload and we also studied the signaling pathways involved in the regulation of antioxidant defenses and neuronal survival. HT22 hippocampal neurons incubated with increasing Cu2+ concentrations (100-250 micromolar) showed decreased glutathione (GSH) levels and GSH peroxidase expression, and increased expression levels of the rate limiting step enzyme for GSH synthesis, glutamate cysteine ligase (GCL). Cu-induced imbalance in antioxidantdefenses generated an increase in reactive oxygen species content. As a result of the increased pro-oxidant conditions, neuronal damage was evidenced by mitochondrial dysfunction and increased lipid peroxidation levels. Mitochondrial function was even more affected by pharmacological inhibition of MAPK (U0126) and PI3K (LY294002) pathways. Both effector kinases, ERK1/2 and Akt, respectively showed a differential neuronal localization and expression levels in neurons exposed to Cu-injury. Our results show that Cu-induced neuronal injury is generated by an imbalance in cellular GSH metabolism and that neuronal survival depends on PI3K/Akt and ERK1/2 mediated pathways.