Membrane-bound beta-amyloid oligomers are recruited into lipid rafts by a fyn-dependent mechanism.
Recently published research indicates that soluble oligomers of beta-amyloid (Abeta) may be the key neurotoxic species associated with the progression of Alzheimer's disease (AD) and that the process of Abeta aggregation may drive this event. Furthermore, soluble oligomers of Abeta 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 Abeta on neuronal plasma membranes where exogenously applied Abeta 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 Abeta 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 Abeta on the neuronal surface was not sufficient to cause cell death but that fyn is required for both the redistribution of Abeta and subsequent cell death. These results identify fyn-dependent Abeta redistribution and accumulation in lipid rafts as being key to ADDL-induced cell death and defines a mechanism by which oligomers of Abeta and tau accumulate in lipid rafts.
Williamson
Ritchie
R
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. ritchie.williamson@iop.kcl.ac.uk
Usardi
Alessia
A
Hanger
Diane P
DP
Anderton
Brian H
BH
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002540:Cerebral Cortex / Q000166:cytology; D006624:Hippocampus / Q000166:cytology; D008024:Ligands; D021962:Membrane Microdomains / Q000378:metabolism*; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn / Q000502:physiology*; D051381:Rats
D016229:Amyloid beta-Peptides; D008024:Ligands; D010446:Peptide Fragments; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn