Amyloid-β Peptide Nitrotyrosination Stabilizes Oligomers and Enhances NMDAR-Mediated Toxicity

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the pathological aggregation of the amyloid-beta peptide (A beta). Monomeric soluble A beta can switch from helicoidal to beta-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 beta 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 beta 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 beta analog containing a single residue (H to E) replacement that mimics the behavior of nitrated A beta 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 beta oligomers was observed. Our results show that A beta nitrotyrosination is a post-translational modification that increases A beta synaptotoxicity.