Prion protein-mediated toxicity of amyloid-β oligomers requires lipid rafts and the transmembrane LRP1
Soluble oligomers of the amyloid-β (Aβ) peptide cause neurotoxicity, synaptic dysfunction and memory impairments which underlie Alzheimers disease (AD). The cellular prion protein (PrPC) was recently identified as a high-affinity neuronal receptor for Aβ oligomers. We report that fibrillar Aβ oligomers recognised by the OC antibody, which have been shown to correlate with the onset and severity of AD, bind preferentially to cells and neurons expressing PrPC. The binding of Aβ oligomers to cell surface PrPC, as well as their downstream activation of Fyn kinase, was dependent on the integrity of cholesterol-rich lipid rafts. In SH-SY5Y cells, fluorescence microscopy and co-localisation with sub-cellular markers revealed that the Aβ oligomers co-internalised with PrPC, accumulated in endosomes and subsequently trafficked to lysosomes. The cell surface binding, internalisation and downstream toxicity of Aβ oligomers was dependent on the transmembrane low density lipoprotein receptor-related protein-1 (LRP1). The binding of Aβ oligomers to cell surface PrPC impaired its ability to inhibit the activity of the β-secretase BACE1 which cleaves the amyloid precursor protein to produce Aβ. The green tea polyphenol (-)-epigallocatechin gallate (EGCG) and the red wine extract resveratrol both re-modelled the fibrillar conformation of Aβ oligomers. The resulting non-fibrillar oligomers displayed significantly reduced binding to PrPC-expressing cells and were no longer cytotoxic. These data indicate that soluble, fibrillar Aβ oligomers bind to PrPC in a conformation-dependent manner and require the integrity of lipid rafts and the transmembrane LRP1 for their cytotoxicity, thus revealing potential targets to alleviate the neurotoxic properties of Aβ oligomers in AD.