CONICET | Buscador de Institutos y Recursos Humanos

The exposure to metal ions such as Fe2+ is considered a potent oxidative damage inducer. This type of oxidative injury is comparable to that of β-amyloid peptide (βA) on the brain of Alzheimers disease patients. In our experimental model, synaptosomes obtained from adult Wistar rats were exposed to FeSO4 (50 μM) for different periods of time (5, 30, and 60 min) and viability parameters and the state of different signal transduction pathways were measured. Mitochondrial function and plasma membrane integrity were affected by the presence of Fe2+ after 5, 30, and 60 min of incubation. Glutamate uptake was impaired only after a 60-min Fe2+-exposure. Synaptosomes and anti-p85 immunoprecipitates (IPs) incubated in the presence of [g-32P]ATP showed an increase in PI3K activity after 5 min of Fe2+-exposure. The increase in Akt phosphorylation in serine 473 and threonine 308 was temporally coincident with PI3K activation. Experiments carried out in the presence of sodium orthovanadate or herbimycin A indicated the involvement of tyrosine phosphorylation in PI3K activation induced by Fe2+. IPs of c-Src demonstrated a strong association between Akt, p-Akt and this tyrosine kinase induced by oxidative stress. Akt downstream effector, GSK3β, was also phosphorylated after 5 and 30 min of iron exposure and this phosphorylation was inhibited by LY294002. Additionally, Erk activation was observed after 5 min of insult exposure, and this activation was also PI3K-dependent. Our results demonstrate that oxidative stress triggers the activation of different synaptic signaling pathways such as PI3K/Akt/GSK3β, c-Src and Erk.