| First Author | Rushworth JV | Year | 2013 |
| Journal | J Biol Chem | Volume | 288 |
| Issue | 13 | Pages | 8935-51 |
| PubMed ID | 23386614 | Mgi Jnum | J:240258 |
| Mgi Id | MGI:5882868 | Doi | 10.1074/jbc.M112.400358 |
| Citation | Rushworth JV, et al. (2013) Prion protein-mediated toxicity of amyloid-beta oligomers requires lipid rafts and the transmembrane LRP1. J Biol Chem 288(13):8935-51 |
| abstractText | Soluble oligomers of the amyloid-beta (Abeta) 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 Abeta oligomers. We report that fibrillar Abeta 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 Abeta 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 Abeta oligomers co-internalized with PrP(C), accumulated in endosomes, and subsequently trafficked to lysosomes. The cell surface binding, internalization, and downstream toxicity of Abeta oligomers was dependent on the transmembrane low density lipoprotein receptor-related protein-1 (LRP1). The binding of Abeta oligomers to cell surface PrP(C) impaired its ability to inhibit the activity of the beta-secretase BACE1, which cleaves the amyloid precursor protein to produce Abeta. The green tea polyphenol (-)-epigallocatechin gallate and the red wine extract resveratrol both remodeled the fibrillar conformation of Abeta 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 Abeta 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 Abeta oligomers in AD. |
