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

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

SUBMITTER: Rushworth JV

PROVIDER: S-EPMC3610967 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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

Rushworth Jo V JV Griffiths Heledd H HH Watt Nicole T NT Hooper Nigel M NM

The Journal of biological chemistry 20130205 13

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 cel ...[more]

PMID: 23386614

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Project description:Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the pathological aggregation of the amyloid-? peptide (A?). Monomeric soluble A? can switch from helicoidal to ?-sheet conformation, promoting its assembly into oligomers and subsequently to amyloid fibrils. Oligomers are highly toxic to neurons and have been reported to induce synaptic transmission impairments. The progression from oligomers to fibrils forming senile plaques is currently considered a protective mechanism to avoid the presence of the highly toxic oligomers. Protein nitration is a frequent post-translational modification under AD nitrative stress conditions. A? can be nitrated at tyrosine 10 (Y10) by peroxynitrite. Based on our analysis of ThT binding, Western blot and electron and atomic force microscopy, we report that A? nitration stabilizes soluble, highly toxic oligomers and impairs the formation of fibrils. We propose a mechanism by which fibril elongation is interrupted upon Y10 nitration: Nitration disrupts fibril-forming folds by preventing H14-mediated bridging, as shown with an A? analog containing a single residue (H to E) replacement that mimics the behavior of nitrated A? related to fibril formation and neuronal toxicity. The pathophysiological role of our findings in AD was highlighted by the study of these nitrated oligomers on mouse hippocampal neurons, where an increased NMDAR-dependent toxicity of nitrated A? oligomers was observed. Our results show that A? nitrotyrosination is a post-translational modification that increases A? synaptotoxicity. SIGNIFICANCE STATEMENT:We report that nitration (i.e., the irreversible addition of a nitro group) of the Alzheimer-related peptide amyloid-? (A?) favors the stabilization of highly toxic oligomers and inhibits the formation of A? fibrils. The nitrated A? oligomers are more toxic to neurons due to increased cytosolic calcium levels throughout their action on NMDA receptors. Sustained elevated calcium levels trigger excitotoxicity, a characteristic event in Alzheimer's disease.

Dataset Information

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

Publications

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

Similar Datasets

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