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

MRC Centre for Neurodegeneration Research, Institute of Psychiatry, King’s College London, UK

¹Correspondence: MRC Centre for Neurodegeneration Research, Department of Neuroscience (Box 037), Institute of Psychiatry, King’s College London, De Crespigny Park, Denmark Hill, London SE5 8AF, UK. E-mail: ritchie.williamson{at}iop.kcl.ac.uk

Recently published research indicates that soluble oligomers of β-amyloid (Aβ) may be the key neurotoxic species associated with the progression of Alzheimer’s disease (AD) and that the process of Aβ aggregation may drive this event. Furthermore, soluble oligomers of Aβ 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 Aβ on neuronal plasma membranes where exogenously applied Aβ 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 Aβ 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 Aβ on the neuronal surface was not sufficient to cause cell death but that fyn is required for both the redistribution of Aβ and subsequent cell death. These results identify fyn-dependent Aβ redistribution and accumulation in lipid rafts as being key to ADDL-induced cell death and defines a mechanism by which oligomers of Aβ and tau accumulate in lipid rafts.—Williamson, R., Usardi, A., Hanger, D. P., Anderton, B. H. Membrane-bound β-amyloid oligomers are recruited into lipid rafts by a fyn-dependent mechanism.

Key Words: Alzheimer’s disease • ADDLs • protein aggregation • tau