Guix Ràfols, Francesc XavierWahle, TinaVennekens, KristelSnellinx, AnChávez Gutiérrez, LucíaIll-Raga, Gerard, 1982-Ramos Fernández, Eva, 1984-Guardia Laguarta, CristinaLleó, AlbertoArimon, MurielBerezovska, OksanaMuñoz López, Francisco José, 1964-Dotti, Carlos G.De Strooper, Bart2015-06-052015-06-052012Guix FX, Wahle T, Vennekens K, Snellinx A, Chavez-Gutiérrez L, Ill-Raga G et al. Modification of y-secretase by nitrosative stress links neuronal ageing to sporadic Alzheimer's disease. EMBO Molecular Medicine. 2012;4(7):660-73. DOI: 10.1002/emmm.2012002431757-4676http://hdl.handle.net/10230/23739Inherited familial Alzheimer's disease (AD) is characterized by small increases in the ratio of Aβ42 versus Aβ40 peptide which is thought to drive the amyloid plaque formation in the brain of these patients. Little is known however whether ageing, the major risk factor for sporadic AD, affects amyloid beta‐peptide (Aβ) generation as well. Here we demonstrate that the secretion of Aβ is enhanced in an in vitro model of neuronal ageing, correlating with an increase in γ‐secretase complex formation. Moreover we found that peroxynitrite (ONOO−), produced by the reaction of superoxide anion with nitric oxide, promoted the nitrotyrosination of presenilin 1 (PS1), the catalytic subunit of γ‐secretase. This was associated with an increased association of the two PS1 fragments, PS1‐CTF and PS1‐NTF, which constitute the active catalytic centre. Furthermore, we found that peroxynitrite shifted the production of Aβ towards Aβ42 and increased the Aβ42/Aβ40 ratio. Our work identifies nitrosative stress as a potential mechanistic link between ageing and AD.application/pdfeng© 2012 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is pRNAAlzheimer, Malaltia d'info:eu-repo/semantics/articlehttp://dx.doi.org/10.1002/emmm.201200243AgeingAlzheimer's diseaseGamma‐secretasePeroxynitritePresenilin‐1info:eu-repo/semantics/openAccess