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-␤ 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.

IP3 receptor mutations and brain diseases in human and rodents

“…; Guivernau et al . ), Aβ is also able to induce IP 3 ‐induced Ca 2+ release. The application of Aβ 25–35 and Aβ 1– 40 induces Ca 2+ release from the ER and consequently triggers apoptosis through the activation of Caspase 3 in cortical neurons (Ferreiro et al .…”

“…Ca 2+ release by Ab Soluble Ab aggregates are toxic to the cells as they promote the elevation of cytosolic Ca 2+ levels Bezprozvanny and Mattson 2008;Agostini and Fasolato 2016). In addition to the Ca 2+ influx through various mechanisms involving the regulation of plasma membrane permeability (Muller et al 1995;Mason et al 1996), formation of intrinsic cation-conducting channels Pollard et al 1993), and activation of nicotinic acetylcholine receptors (Wang et al 2000) and glutamate receptor channels (De Felice et al 2007;Alberdi et al 2010;Guivernau et al 2016), Ab is also able to induce IP 3 -induced Ca 2+ release. The application of Ab 25-35 and Ab 1-40 induces Ca 2+ release from the ER and consequently triggers apoptosis through the activation of Caspase 3 in cortical neurons (Ferreiro et al 2004).…”

Factors affecting the physical stability (aggregation) of peptide therapeutics

“…In addition, phosphorylation of Ab has been shown to increase oligomer formation [151][152][153], while citrullination of Ab decreases the rate of fibril formation but may increase the amount of toxic oligomers [154]. Similarly, nitration has also been shown to increase the amount of oligomers of Ab in solution [155]. Backbone modification of Ab at Gly29 also shows decreased fibril formation and increased oligomer formation [156].…”

Brain interference: Revisiting the role of IFNγ in the central nervous system

“…Imbalances in glutamatergic transmission can lead to the generation of seizures and/or to excitotoxicity that is characterized by the high influx of calcium ions, which triggers an enzymatic cascade that culminates in neuronal damage by overexcitation. Excitoxicity is a common underlying mechanism of neurodegenerative diseases such Alzheimer's (Guivernau et al, 2016;Scimemi et al, 2013), Parkinson's (Armentero et al, 2006;Hoekstra et al, 2015;Van Laar et al, 2015) and Multiple Sclerosis (Pitt et al, 2000), among others.…”