Membrane-bound β-amyloid oligomers are recruited into lipid rafts by a fyn-dependent mechanism

Recently published research indicates that soluble oligomers of beta-amyloid (AD) may be the key neurotoxic species associated with the progression of Alzheimer's disease (AD) and that the process of AD aggregation may drive this event. Furthermore, soluble oligomers of AD 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 AD on neuronal plasma membranes where exogenously applied AD in the form of ADDLs can be trafficked on the neuronal membrane and accumulate in lipid rafts. ADDI-induced dynamic alterations in lipid raft protein composition were found to facilitate this movement. We show clear associations between AD 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 AD on the neuronal surface was not sufficient to cause cell death but that fyn is required for both the redistribution of AD and subsequent cell death. These results identify fyn-dependent AD redistribution and accumulation in lipid rafts as being key to ADDL-induced cell death and defines a mechanism by which oligomers of AD and tau accumulate in lipid rafts.