RGD Reference Report - Prion protein-mediated toxicity of amyloid-ß oligomers requires lipid rafts and the transmembrane LRP1. - Rat Genome Database

Send us a Message



Submit Data |  Help |  Video Tutorials |  News |  Publications |  Download |  REST API |  Citing RGD |  Contact   

Prion protein-mediated toxicity of amyloid-ß oligomers requires lipid rafts and the transmembrane LRP1.

Authors: Rushworth, Jo V  Griffiths, Heledd H  Watt, Nicole T  Hooper, Nigel M 
Citation: Rushworth JV, etal., J Biol Chem. 2013 Mar 29;288(13):8935-51. doi: 10.1074/jbc.M112.400358. Epub 2013 Feb 5.
RGD ID: 12910992
Pubmed: (View Article at PubMed) PMID:23386614
DOI: Full-text: DOI:10.1074/jbc.M112.400358

Soluble oligomers of the amyloid-ß (Aß) 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 Aß oligomers. We report that fibrillar Aß 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 Aß 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 Aß oligomers co-internalized with PrP(C), accumulated in endosomes, and subsequently trafficked to lysosomes. The cell surface binding, internalization, and downstream toxicity of Aß oligomers was dependent on the transmembrane low density lipoprotein receptor-related protein-1 (LRP1). The binding of Aß oligomers to cell surface PrP(C) impaired its ability to inhibit the activity of the ß-secretase BACE1, which cleaves the amyloid precursor protein to produce Aß. The green tea polyphenol (-)-epigallocatechin gallate and the red wine extract resveratrol both remodeled the fibrillar conformation of Aß 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 Aß 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 Aß oligomers in AD.

Annotation

Gene Ontology Annotations    

Biological Process

Objects Annotated

Genes (Rattus norvegicus)
Prnp  (prion protein)


Additional Information