Amyloid-lowering isocoumarins are not direct inhibitors of γ-secretase (original) (raw)

Nature Cell Biology volume 4, pages E110–E111 (2002)Cite this article

To the Editor

The last step in the production of the amyloid-β protein (Aβ), the major protein component of the cerebral plaques of Alzheimer's disease, is proteolysis within the transmembrane region of the Amyloid-β Precursor Protein (APP) by γ-secretase. The Notch receptor (N) is processed in a similar manner as part of a signalling mechanism essential for metazoan development. Missense mutations in the polytopic presenilins, PS1 and PS2, cause Alzheimer's disease and alter the specificity of γ-secretase to increase production of a much more aggregation-prone form of Aβ1. Knockout studies, site-directed mutagenesis, pharmacological profiling, affinity labelling and biochemical isolation all strongly support the hypothesis that γ-secretase is a complex of integral membrane proteins, an aspartyl protease in which the active site resides between the two subunits of a processed form of PS2,3. As a corollary, PS processes both APP and N.

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Figure 1: Effect of isocoumarins on γ-secretase and PS.

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Authors and Affiliations

  1. Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, Boston, 02115, MA, USA
    William P. Esler, Chittaranjan Das, William A. Campbell, W. Taylor Kimberly, Anna Y. Kornilova, Thekla S. Diehl, Wenjuan Ye, Beth L. Ostaszewski, Weiming Xia, Dennis J. Selkoe & Michael S. Wolfe

Authors

  1. William P. Esler
  2. Chittaranjan Das
  3. William A. Campbell
  4. W. Taylor Kimberly
  5. Anna Y. Kornilova
  6. Thekla S. Diehl
  7. Wenjuan Ye
  8. Beth L. Ostaszewski
  9. Weiming Xia
  10. Dennis J. Selkoe
  11. Michael S. Wolfe

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Esler, W., Das, C., Campbell, W. et al. Amyloid-lowering isocoumarins are not direct inhibitors of γ-secretase.Nat Cell Biol 4, E110–E111 (2002). https://doi.org/10.1038/ncb0502-e110b

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