Deposition of amyloid-beta (Abeta) peptides into specific encephalic structures has been pointed as an important event related to Alzheimer s disease pathogenesis and associated with activation of glial cells, neuroinflammation, oxidative responses, and cognitive deficits. Abeta-induced pro-oxidative damage may regulate the activity of glutamate transporters, leading to reduced glutamate uptake and, as a consequence, excitotoxic events. Herein, we evaluated the effects of the pretreatment of atorvastatin, a HMG-CoA reductase inhibitor, on behavioral and biochemical alterations induced by a single intracerebroventricular (i.c.v.) injection of aggregated Abeta1-40 in mice. Atorvastatin (10 mg/kg/day, p.o.) was administered through seven consecutive days before Abeta1-40 administration. Abeta1-40 caused significant cognitive impairment in the object-place recognition task (2 weeks after the i.c.v. injection) and this phenomenon was abolished by atorvastatin pretreatment. Ex vivo evaluation of glutamate uptake into hippocampal and cerebral cortices slices showed atorvastatin, and Abeta1-40 decreased hippocampal and cortical Na(+)-dependent glutamate uptake. However, Abeta1-40 increased Na(+)-independent glutamate uptake and it was prevented by atorvastatin in prefrontal cortex slices. Moreover, Abeta1-40 treatment significantly increased the cerebrocortical activities of glutathione reductase and glutathione peroxidase and these events were blunted by atorvastatin pretreatment. Reduced or oxidized glutathione levels were not altered by Abeta1-40 and/or atorvastatin treatment. These results extend the notion of the protective action of atorvastatin against neuronal toxicity induced by Abeta1-40 demonstrating that a pretreatment with atorvastatin prevents the spatial learning and memory deficits induced by Abeta in rodents and promotes changes in glutamatergic and antioxidant systems mainly in prefrontal cortex.