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Title: Modification of γ-secretase by nitrosative stress links neuronal ageing to sporadic Alzheimer's disease
Authors: Guix, Francesc
Wahle, Tina
Vennekens, Kristel
Snellinx, An
Chavez Gutierrez, Lucia
Ill-Raga, Gerard
Ramos-Fernandez, Eva
Guardia-Laguarta, Cristina
Lleó, Alberto
Arimon, Muriel
Berezovska, Oksana
Muñoz, Francisco J
Dotti, Carlos
De Strooper, Bart # ×
Issue Date: Jul-2012
Publisher: Wiley-Blackwell Publishing Ltd.
Series Title: EMBO Molecular Medicine vol:4 issue:7 pages:660-673
Abstract: 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.
ISSN: 1757-4676
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Neuronal Differentiation
Laboratory for the Research of Neurodegenerative Diseases
Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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