Aggregation of beta -amyloid protein (AI?) to form oligomers is considered to be a key step in generating neurotoxicity in the Alzheimera??s disease (AD) brain. Agents that bind to A beta and inhibit oligomerization have been proposed as AD therapeutics. In this study, we investigated the binding of fluorescein-labelled A beta 1-42 (FluoA beta 1-42) to SH-SY5Y neuroblastoma cells and examined the effect of the 39 kDa receptor-associated protein (RAP), on the A beta -cell interaction. FluoA beta 1-42 bound to the cells in a punctate pattern. Surprisingly, when RAP was added to the incubations, FluoA beta 1-42 and RAP were found to be co-localized on the cell surface, suggesting that RAP and A beta may bind to each other. Experiments using the purified proteins confirmed that a RAP-A beta complex was stable and resistant to sodium dodecyl sulfate. RAP also inhibited A beta oligomerization. We next examined whether RAP could inhibit the neurotoxic effects of A beta . Addition of A beta 1-42 to SH-SY5Y cells caused an increase in intracellular Ca2+ that was inhibited by treatment of the AI? peptide with RAP. RAP also blocked an AI?-induced inhibition of long-term memory consolidation in one-day-old chicks. This study demonstrates that RAP binds to A beta and is an inhibitor of the neurotoxic effects of A beta .