title: Modification of γ-secretase by nitrosative stress links neuronal ageing to sporadic Alzheimer's disease.
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.
authors.affiliation: VIB Center for Biology of Disease - VIB, Leuven, Belgium.
authors.forename: Francesc X
authors.initials: FX
authors.lastname: Guix
authors.forename: Tina
authors.initials: T
authors.lastname: Wahle
authors.forename: Kristel
authors.initials: K
authors.lastname: Vennekens
authors.forename: An
authors.initials: A
authors.lastname: Snellinx
authors.forename: Lucía
authors.initials: L
authors.lastname: Chávez-Gutiérrez
authors.forename: Gerard
authors.initials: G
authors.lastname: Ill-Raga
authors.forename: Eva
authors.initials: E
authors.lastname: Ramos-Fernandez
authors.forename: Cristina
authors.initials: C
authors.lastname: Guardia-Laguarta
authors.forename: Alberto
authors.initials: A
authors.lastname: Lleó
authors.forename: Muriel
authors.initials: M
authors.lastname: Arimon
authors.forename: Oksana
authors.initials: O
authors.lastname: Berezovska
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Muñoz
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Dotti
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D020134:Catalytic Domain; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D006801:Humans; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000494:pharmacology*; D053764:Presenilin-1 / Q000737:chemistry / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012307:Risk Factors; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000099156:Superoxide Dismutase 2
chemical_list: D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D030421:Peroxynitrous Acid; D053764:Presenilin-1; D034741:RNA, Small Interfering; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)