title: Amyloid-β Peptide Nitrotyrosination Stabilizes Oligomers and Enhances NMDAR-Mediated Toxicity.
abstract: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the pathological aggregation of the amyloid-β peptide (Aβ). Monomeric soluble Aβ can switch from helicoidal to β-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. Aβ 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 Aβ 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 Aβ analog containing a single residue (H to E) replacement that mimics the behavior of nitrated Aβ 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 Aβ oligomers was observed. Our results show that Aβ nitrotyrosination is a post-translational modification that increases Aβ synaptotoxicity.
  
  
  
  We report that nitration (i.e., the irreversible addition of a nitro group) of the Alzheimer-related peptide amyloid-β (Aβ) favors the stabilization of highly toxic oligomers and inhibits the formation of Aβ fibrils. The nitrated Aβ 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.
authors.affiliation: Laboratory of Molecular Physiology, Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Biuse
authors.identifier: 0000-0002-7176-4783
authors.initials: B
authors.lastname: Guivernau
authors.affiliation: Laboratory of Structural Bioinformatics, Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Jaume
authors.identifier: 0000-0001-5210-4387
authors.initials: J
authors.lastname: Bonet
authors.affiliation: Laboratory of Molecular Physiology, Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Victòria
authors.initials: V
authors.lastname: Valls-Comamala
authors.affiliation: Laboratory of Molecular Physiology, Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Mònica
authors.initials: M
authors.lastname: Bosch-Morató
authors.affiliation: Center on Aging and Regeneration, Departamento de Biología Celular y Molecular, P. Universidad Católica de Chile, 8320000 Chile.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Godoy
authors.affiliation: Center on Aging and Regeneration, Departamento de Biología Celular y Molecular, P. Universidad Católica de Chile, 8320000 Chile.|Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, NSW 2031 Sydney, Australia.
authors.forename: Nibaldo C
authors.initials: NC
authors.lastname: Inestrosa
authors.affiliation: Unitat de Biofísica, Departament de Bioquímica i de Biologia Molecular, Facultat de Medicina, and Centre d'Estudis en Biofísica, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
authors.forename: Alex
authors.identifier: 0000-0002-3457-0875
authors.initials: A
authors.lastname: Perálvarez-Marín
authors.affiliation: Nanomalaria Joint Group, Institute for Bioengineering of Catalonia and Barcelona Institute for Global Health, 08036 Barcelona, Spain, and.
authors.forename: Xavier
authors.initials: X
authors.lastname: Fernández-Busquets
authors.affiliation: Laboratory of Proteomics and Protein Chemistry, Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: David
authors.identifier: 0000-0002-6317-6666
authors.initials: D
authors.lastname: Andreu
authors.affiliation: Laboratory of Structural Bioinformatics, Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Baldomero
authors.identifier: 0000-0003-0702-0250
authors.initials: B
authors.lastname: Oliva
authors.affiliation: Laboratory of Molecular Physiology, Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain, paco.munoz@upf.edu.
authors.forename: Francisco J
authors.identifier: 0000-0002-1343-3599
authors.initials: FJ
authors.lastname: Muñoz
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D000818:Animals; D001665:Binding Sites; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D003198:Computer Simulation; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009574:Nitro Compounds / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000378:metabolism*; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D009574:Nitro Compounds; D016194:Receptors, N-Methyl-D-Aspartate; D014443:Tyrosine
keywords: Alzheimer; NMDA Rc; amyloid; nitrotyrosination; oligomers; peroxynitrite