In the genesis of Alzheimer's disease (AD), converging lines of evidence suggest that amyloid-β peptide (Aβ) triggers a pathogenic cascade leading to neuronal loss. It was long assumed that Aβ had to be assembled into extracellular amyloid fibrils or aggregates to exert its cytotoxic effects. Over the past decade, characterization of soluble oligomeric Aβ species in the brains of AD patients and in transgenic models has raised the possibility that different conformations of Aβ may contribute to AD pathology via different mechanisms. The receptor for advanced glycation end products (RAGE), a member of the Ig superfamily, is a cellular binding site for Aβ. Here, we investigate the role of RAGE in apoptosis induced by distinct well characterized Aβ conformations: Aβ oligomers (AβOs), Aβ fibrils (AβFs), and Aβ aggregates (AβAs). In our in vitro system, treatment with polyclonal anti-RAGE antibodies significantly improves SHSY-5Y cell and neuronal survival exposed to either AβOs or AβAs but does not affect AβF toxicity. Interestingly, using site-specific antibodies, we demonstrate that targeting of the V_d domain of RAGE attenuates AβO-induced toxicity in both SHSY-5Y cells and rat cortical neurons, whereas inhibition of AβA-induced apoptosis requires the neutralization of the C_1d domain of the receptor. Thus, our data indicate that distinct regions of RAGE are involved in Aβ-induced cellular and neuronal toxicity with respect to the Aβ aggregation state, and they suggest the blockage of particular sites of the receptor as a potential therapeutic strategy to attenuate neuronal death.