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

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, affe...

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Detalles Bibliográficos
Autores: Guix Ràfols, Francesc Xavier, Wahle, Tina, Vennekens, Kristel, Snellinx, An, Chávez Gutiérrez, Lucía, Ill-Raga, Gerard, 1982-, Ramos Fernández, Eva, 1984-, Guardia Laguarta, Cristina, Lleó, Alberto, Arimon, Muriel, Berezovska, Oksana, Muñoz López, Francisco José, 1964-, Dotti, Carlos G., De Strooper, Bart
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2012
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10230/23739
Acceso en línea:http://hdl.handle.net/10230/23739
http://dx.doi.org/10.1002/emmm.201200243
Access Level:acceso abierto
Palabra clave:RNA
Alzheimer, Malaltia d&apos
Ageing
Alzheimer&apos
s disease
Gamma‐secretase
Peroxynitrite
Presenilin‐1
Descripción
Sumario: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 Aβ42 and increased the Aβ42/Aβ40 ratio. Our work identifies nitrosative stress as a potential mechanistic link between ageing and AD.

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