title: Prion protein-mediated toxicity of amyloid-β oligomers requires lipid rafts and the transmembrane LRP1.
abstract: Soluble oligomers of the amyloid-β (Aβ) peptide cause neurotoxicity, synaptic dysfunction, and memory impairments that underlie Alzheimer disease (AD). The cellular prion protein (PrP(C)) was recently identified as a high affinity neuronal receptor for Aβ oligomers. We report that fibrillar Aβ oligomers recognized by the OC antibody, which have been shown to correlate with the onset and severity of AD, bind preferentially to cells and neurons expressing PrP(C). The binding of Aβ oligomers to cell surface PrP(C), 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-localization with subcellular markers revealed that the Aβ oligomers co-internalized with PrP(C), accumulated in endosomes, and subsequently trafficked to lysosomes. The cell surface binding, internalization, 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 PrP(C) 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 and the red wine extract resveratrol both remodeled the fibrillar conformation of Aβ oligomers. The resulting nonfibrillar oligomers displayed significantly reduced binding to PrP(C)-expressing cells and were no longer cytotoxic. These data indicate that soluble, fibrillar Aβ oligomers bind to PrP(C) 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.
authors: School of Molecular and Cellular Biology, Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, United Kingdom.
authors: Jo V
authors: JV
authors: Rushworth
authors: Heledd H
authors: HH
authors: Griffiths
authors: Nicole T
authors: NT
authors: Watt
authors: Nigel M
authors: NM
authors: Hooper
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002392:Catechin / Q000031:analogs & derivatives / Q000737:chemistry; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000737:chemistry*; D021962:Membrane Microdomains / Q000737:chemistry* / Q000378:metabolism*; D008856:Microscopy, Fluorescence / Q000379:methods; D009474:Neurons / Q000378:metabolism; D011328:Prions / Q000737:chemistry*; D011485:Protein Binding; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D017208:Rats, Wistar; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology; D013662:Tea / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D011328:Prions; D013267:Stilbenes; D013662:Tea; D002392:Catechin; C045651:epigallocatechin gallate; D051076:Proto-Oncogene Proteins c-fyn; D053148:Caspase 3; D000077185:Resveratrol
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