Modification of gamma-secretase by nitrosative stress links neuronal ageing to sporadic Alzheimer's disease

Francesc X. Guix, Tina Wahle, Kristel Vennekens, An Snellinx, Lucia Chavez-Gutierrez, Gerard Ill-Raga, Eva Ramos-Fernandez, Cristina Guardia-Laguarta, Alberto Lleo, Muriel Arimon, Oksana Berezovska, Francisco J. Munoz, Carlos G. Dotti, Bart De Strooper

Research output: Indexed journal article Articlepeer-review

68 Citations (Scopus)


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 Aβ 42 and increased the Aβ 42/Aβ 40 ratio. Our work identifies nitrosative stress as a potential mechanistic link between ageing and AD.

Original languageEnglish
Pages (from-to)660-673
Number of pages14
JournalEMBO Molecular Medicine
Issue number7
Publication statusPublished - Jul 2012
Externally publishedYes


  • Ageing
  • Alzheimer's disease
  • Gamma-secretase
  • Peroxynitrite
  • Presenilin-1


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