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

Authors

  • Francesc X. Guix,

    1. VIB Center for Biology of Disease – VIB, Leuven, Belgium
    2. Center of Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KULeuven, Leuven, Gasthuisberg O&N, Belgium
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  • Tina Wahle,

    1. VIB Center for Biology of Disease – VIB, Leuven, Belgium
    2. Center of Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KULeuven, Leuven, Gasthuisberg O&N, Belgium
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  • Kristel Vennekens,

    1. VIB Center for Biology of Disease – VIB, Leuven, Belgium
    2. Center of Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KULeuven, Leuven, Gasthuisberg O&N, Belgium
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  • An Snellinx,

    1. VIB Center for Biology of Disease – VIB, Leuven, Belgium
    2. Center of Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KULeuven, Leuven, Gasthuisberg O&N, Belgium
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  • Lucía Chávez-Gutiérrez,

    1. VIB Center for Biology of Disease – VIB, Leuven, Belgium
    2. Center of Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KULeuven, Leuven, Gasthuisberg O&N, Belgium
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  • Gerard Ill-Raga,

    1. Laboratory of Molecular Physiology and Channelopathies, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
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  • Eva Ramos-Fernandez,

    1. Laboratory of Molecular Physiology and Channelopathies, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
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  • Cristina Guardia-Laguarta,

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

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

    1. Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Charlestown, MA, USA
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  • Oksana Berezovska,

    1. Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Charlestown, MA, USA
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  • Francisco J. Muñoz,

    1. Laboratory of Molecular Physiology and Channelopathies, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
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  • Carlos G. Dotti,

    Corresponding author
    1. VIB Center for Biology of Disease – VIB, Leuven, Belgium
    2. Center of Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KULeuven, Leuven, Gasthuisberg O&N, Belgium
    3. Centro de Biología Molecular Severo Ochoa (CSIC/UAM), Madrid, Spain
    • Carlos G. Dotti, Tel: +32 16 330519; Fax: +32 16 330522

      Bart De Strooper, Tel: +32 16 346227; Fax: +32 16 347181

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  • Bart De Strooper

    Corresponding author
    1. VIB Center for Biology of Disease – VIB, Leuven, Belgium
    2. Center of Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KULeuven, Leuven, Gasthuisberg O&N, Belgium
    • Carlos G. Dotti, Tel: +32 16 330519; Fax: +32 16 330522

      Bart De Strooper, Tel: +32 16 346227; Fax: +32 16 347181

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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.

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