Hypoxic condition may be the cause of progressive alterations in Alzheimer's disease (AD). Our hypothesis is that ischemia activates the Receptor for Advanced Glycation Endproducts (RAGE) in different cell targets, leading to synaptic dysfunction. RAGE can bind beta-amyloid (Ab), and its expression is altered under ischemic conditions. We recorded Field-EPSP in entorhinal cortex (EC) slices that were exposed to oxygen-glucose deprivation (OGD. We investigated the effects of OGD in: slices treated with blocking anti-RAGE IgGs, slices from RAGE (-/-) or transgenic (Tg) mice in which defective RAGE is expressed selectively in neurons (DN-RAGE) or in microglia (DNMSR). To test whether Ab enriched environment increases synaptic dysfunction induced by OGD, we evaluated slices treated with b-amyloid (Ab) or slices from TgAPP. In slices exposed to OGD we observed a long lasting depression of fEPSPs amplitude. Absence of RAGE in RAGE (-/-) slices resulted in a complete recover of fEPSPs amplitude following OGD. The same protective effect was achieved in Tg DNMSR slices but not in slices from Tg DN-RAGE mice. Moreover, we found that the effects of OGD were enhanced in Ab perfused or Tg APP slices. The absence of RAGE or selective deficiency of RAGE in microglia (DNMSR) protected from synaptic impairment induced by either Ab alone or Ab coupled to OGD. Our results indicate cell-specific contribution of RAGE to the effects of ischemia on synaptic function in Ab enriched environment.