Research Article

You have full text access to this OnlineOpen article

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

  1. Francesc X. Guix1,2,
  2. Tina Wahle1,2,
  3. Kristel Vennekens1,2,
  4. An Snellinx1,2,
  5. Lucía Chávez-Gutiérrez1,2,
  6. Gerard Ill-Raga3,
  7. Eva Ramos-Fernandez3,
  8. Cristina Guardia-Laguarta4,
  9. Alberto Lleó4,
  10. Muriel Arimon5,
  11. Oksana Berezovska5,
  12. Francisco J. Muñoz3,
  13. Carlos G. Dotti1,2,6,*,
  14. Bart De Strooper1,2,*

Article first published online: 2 MAY 2012

DOI: 10.1002/emmm.201200243

Issue

EMBO Molecular Medicine

EMBO Molecular Medicine

Volume 4, Issue 7, pages 660–673, July 2012

Additional Information

How to Cite

Guix, F. X., Wahle, T., Vennekens, K., Snellinx, A., Chávez-Gutiérrez, L., Ill-Raga, G., Ramos-Fernandez, E., Guardia-Laguarta, C., Lleó, A., Arimon, M., Berezovska, O., Muñoz, F. J., Dotti, C. G. and De Strooper, B. (2012), Modification of γ-secretase by nitrosative stress links neuronal ageing to sporadic Alzheimer's disease. EMBO Mol Med, 4: 660–673. doi: 10.1002/emmm.201200243

Author Information

  1. 1

    VIB Center for Biology of Disease – VIB, Leuven, Belgium

  2. 2

    Center of Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KULeuven, Leuven, Gasthuisberg O&N, Belgium

  3. 3

    Laboratory of Molecular Physiology and Channelopathies, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain

  4. 4

    Alzheimer Laboratory, Neurology Department, Hospital de la Santa Creu i Sant Pau, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain

  5. 5

    Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Charlestown, MA, USA

  6. 6

    Centro de Biología Molecular Severo Ochoa (CSIC/UAM), Madrid, Spain

*Tel: +32 16 330519; Fax: +32 16 330522

Publication History

  1. Issue published online: 3 JUL 2012
  2. Article first published online: 2 MAY 2012
  3. Accepted manuscript online: 10 APR 2012 05:10AM EST
  4. Manuscript Revised: 30 MAR 2012
  5. Manuscript Accepted: 30 MAR 2012
  6. Manuscript Received: 6 DEC 2011

Funded by

  • NIH. Grant Number: AG15379

SEARCH

SEARCH BY CITATION

ARTICLE TOOLS

View Full Article with Supporting Information (HTML) Get PDF (992K)

Keywords:

  • ageing;
  • Alzheimer's disease;
  • gamma-secretase;
  • peroxynitrite;
  • presenilin-1

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 Aβ42 and increased the Aβ42/Aβ40 ratio. Our work identifies nitrosative stress as a potential mechanistic link between ageing and AD.

View Full Article with Supporting Information (HTML) Get PDF (992K)