Recently published research indicates that soluble oligomers of -amyloid (A) may be the key neurotoxic species associated with the progression of Alzheimer's disease (AD) and that the process of A aggregation may drive this event. Furthermore, soluble oligomers of A and tau accumulate in the lipid rafts of brains from AD patients through an as yet unknown mechanism. Using cell culture models we report a novel action of A on neuronal plasma membranes where exogenously applied A in the form of ADDLs can be trafficked on the neuronal membrane and accumulate in lipid rafts. ADDL-induced dynamic alterations in lipid raft protein composition were found to facilitate this movement. We show clear associations between A accumulation and redistribution on the neuronal membrane and alterations in the protein composition of lipid rafts. In addition, our data from fyn^-/- transgenic mice show that accumulation of A on the neuronal surface was not sufficient to cause cell death but that fyn is required for both the redistribution of A and subsequent cell death. These results identify fyn-dependent A redistribution and accumulation in lipid rafts as being key to ADDL-induced cell death and defines a mechanism by which oligomers of A and tau accumulate in lipid rafts.—Williamson, R., Usardi, A., Hanger, D. P., Anderton, B. H. Membrane-bound -amyloid oligomers are recruited into lipid rafts by a fyn-dependent mechanism.