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Substrate-targeting γ-secretase modulators

Author

Listed:
  • Thomas L. Kukar

    (Mayo Clinic, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA)

  • Thomas B. Ladd

    (Mayo Clinic, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA)

  • Maralyssa A. Bann

    (Mayo Clinic, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA)

  • Patrick C. Fraering

    (Brain Mind Institute and School of Life Sciences, Swiss Federal Institute of Technology (EPFL)
    Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA)

  • Rajeshwar Narlawar

    (Clemens Schöpf-Institute of Chemistry and Biochemistry, Technische Universitaet Darmstadt, Petersenstr. 22, D-64287 Darmstadt, Germany)

  • Ghulam M. Maharvi

    (Mayo Clinic, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA)

  • Brent Healy

    (Mayo Clinic, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA)

  • Robert Chapman

    (Mayo Clinic, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA)

  • Alfred T. Welzel

    (Laboratory for Neurodegenerative Research, Conway Institute University College Dublin)

  • Robert W. Price

    (Mayo Clinic, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA)

  • Brenda Moore

    (Mayo Clinic, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA)

  • Vijayaraghavan Rangachari

    (Mayo Clinic, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA)

  • Bernadette Cusack

    (Mayo Clinic, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA)

  • Jason Eriksen

    (Mayo Clinic, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA)

  • Karen Jansen-West

    (Mayo Clinic, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA)

  • Christophe Verbeeck

    (Mayo Clinic, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA)

  • Debra Yager

    (Mayo Clinic, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA)

  • Christopher Eckman

    (Mayo Clinic, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA)

  • Wenjuan Ye

    (Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA)

  • Sarah Sagi

    (University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA)

  • Barbara A. Cottrell

    (University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA)

  • Justin Torpey

    (University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA)

  • Terrone L. Rosenberry

    (Mayo Clinic, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA)

  • Abdul Fauq

    (Mayo Clinic, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA)

  • Michael S. Wolfe

    (Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA)

  • Boris Schmidt

    (Clemens Schöpf-Institute of Chemistry and Biochemistry, Technische Universitaet Darmstadt, Petersenstr. 22, D-64287 Darmstadt, Germany)

  • Dominic M. Walsh

    (Laboratory for Neurodegenerative Research, Conway Institute University College Dublin)

  • Edward H. Koo

    (University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA)

  • Todd E. Golde

    (Mayo Clinic, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA)

Abstract

Alzheimer's disease: γ-secretase modulators target Aβ42 One promising approach to Alzheimer's disease treatment involves the use of drugs to reduce the rate of deposition of Aβ42, the 42-residue form of amyloid-β peptide, by curbing its generation. Certain non-steroidal anti-inflammatory drugs known as γ-secretase modulators or GSMs, including ibuprofen and sulindac, have this capacity but how they work is unclear. Now their target has been identified as a site on Aβ42 itself — rather than the presenilins or a core β-secretase component. By binding to Aβ42 these drugs inhibit not only its rate of production but also its aggregation.

Suggested Citation

  • Thomas L. Kukar & Thomas B. Ladd & Maralyssa A. Bann & Patrick C. Fraering & Rajeshwar Narlawar & Ghulam M. Maharvi & Brent Healy & Robert Chapman & Alfred T. Welzel & Robert W. Price & Brenda Moore &, 2008. "Substrate-targeting γ-secretase modulators," Nature, Nature, vol. 453(7197), pages 925-929, June.
    • Handle: RePEc:nat:nature:v:453:y:2008:i:7197:d:10.1038_nature07055
    DOI: 10.1038/nature07055
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