Prion Protein-mediated Toxicity of Amyloid-β Oligomers Requires Lipid Rafts and the Transmembrane LRP1

Soluble oligomers of the amyloid-beta (A beta) peptide cause neurotoxicity, synaptic dysfunction, and memory impairments that underlie Alzheimer disease (AD). The cellular prion protein (PrPC) was recently identified as a high affinity neuronal receptor for A beta oligomers. We report that fibrillar A beta 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 PrPC. The binding of A beta 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-localization with subcellular markers revealed that the A beta oligomers co-internalized with PrPC, accumulated in endosomes, and subsequently trafficked to lysosomes. The cell surface binding, internalization, and downstream toxicity of A beta oligomers was dependent on the transmembrane low density lipoprotein receptor-related protein-1 (LRP1). The binding of A beta oligomers to cell surface PrPC impaired its ability to inhibit the activity of the beta-secretase BACE1, which cleaves the amyloid precursor protein to produce A beta. The green tea polyphenol (-)-epigallo-catechin gallate and the red wine extract resveratrol both remodeled the fibrillar conformation of A beta oligomers. The resulting nonfibrillar oligomers displayed significantly reduced binding to PrPC-expressing cells and were no longer cytotoxic. These data indicate that soluble, fibrillar A beta 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 A beta oligomers in AD.