Inherited 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.

This work was made possible by grants from the Fund for Scientific Research, Flanders; the K.U.Leuven; the VIB, Methusalem (K.U.Leuven and the Flemisch government), the Foundation for Alzheimer Research (SAO/FRMA), the European Research council (BDS), NIH AG15379 (OB), Spanish Ministry of Science and Innovation SAF 2010‐14906, Consolider 2010‐00045 (CGD), Spanish Ministery of Health (Fondo de Investigación Sanitaria‐PI10/00587 and Red HERACLES RD06/0009); The European FEDER Fundings; and Fundació La Marató de TV3 (Catalonia; Spain; no. 100310). We would like to acknowledge the Banc de Teixits Neurologics de l' Hospital Clinic de Barcelona and the Unidad de Neuropatología y Banco de Cerebros of Fundación Hospital Alcorcón for providing the brain samples. BDS is the Arthur Bax and Anna Vanluffelen chair for AD. FG obtained a IEF fellowship of the Marie Curie Actions program in FP7 and a Beatriu de Pinos grant of the Generalitat de Catalunya, Spain. TW was supported by EMBO and DFG long‐term fellowships