Open AccessModification of γ‐secretase by nitrosative stress links neuronal ageing to sporadic Alzheimer's disease
Author(s) -
Guix Francesc X.,
Wahle Tina,
Vennekens Kristel,
Snellinx An,
ChávezGutiérrez Lucía,
IllRaga Gerard,
RamosFernandez Eva,
GuardiaLaguarta Cristina,
Lleó Alberto,
Arimon Muriel,
Berezovska Oksana,
Muñoz Francisco J.,
Dotti Carlos G.,
De Strooper Bart
Publication year - 2012
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201200243
Subject(s) - peroxynitrite , presenilin , ageing , nitric oxide , chemistry , superoxide , protein subunit , alzheimer's disease , amyloid (mycology) , amyloid precursor protein , microbiology and biotechnology , biochemistry , biology , medicine , disease , enzyme , inorganic chemistry , organic chemistry , gene
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.