Modification of γ-secretase by nitrosative stress links neuronal ageing to sporadic Alzheimer's disease.
EMBO Mol Med
; 4(7): 660-73, 2012 Jul.
Article
in En
| MEDLINE
| ID: mdl-22488900
ABSTRACT
Inherited familial Alzheimer's disease (AD) is characterized by small increases in the ratio of Aß42 versus Aß40 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 (Aß) generation as well. Here we demonstrate that the secretion of Aß 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 Aß towards Aß(42) and increased the Aß(42) /Aß(40) ratio. Our work identifies nitrosative stress as a potential mechanistic link between ageing and AD.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Cellular Senescence
/
Peroxynitrous Acid
/
Amyloid Precursor Protein Secretases
/
Alzheimer Disease
/
Neurons
Type of study:
Etiology_studies
/
Prognostic_studies
/
Risk_factors_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
EMBO Mol Med
Journal subject:
BIOLOGIA MOLECULAR
Year:
2012
Document type:
Article
Affiliation country:
Belgium