Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation

J Biol Chem. 2004 Mar 26;279(13):12876-82. doi: 10.1074/jbc.M311652200. Epub 2004 Jan 6.


Inhibition of gamma-secretase, one of the enzymes responsible for the cleavage of the amyloid precursor protein (APP) to produce the pathogenic beta-amyloid (Abeta) peptides, is an attractive approach to the treatment of Alzheimer disease. In addition to APP, however, several other gamma-secretase substrates have been identified (e.g. Notch), and altered processing of these substrates by gamma-secretase inhibitors could lead to unintended biological consequences. To study the in vivo consequences of gamma-secretase inhibition, the gamma-secretase inhibitor LY-411,575 was administered to C57BL/6 and TgCRND8 APP transgenic mice for 15 days. Although most tissues were unaffected, doses of LY-411,575 that inhibited Abeta production had marked effects on lymphocyte development and on the intestine. LY-411,575 decreased overall thymic cellularity and impaired intrathymic differentiation at the CD4(-)CD8(-)CD44(+)CD25(+) precursor stage. No effects on peripheral T cell populations were noted following LY-411,575 treatment, but evidence for the altered maturation of peripheral B cells was observed. In the intestine, LY-411,575 treatment increased goblet cell number and drastically altered tissue morphology. These effects of LY-411,575 were not seen in mice that were administered LY-D, a diastereoisomer of LY-411,575, which is a very weak gamma-secretase inhibitor. These studies show that inhibition of gamma-secretase has the expected benefit of reducing Abeta in a murine model of Alzheimer disease but has potentially undesirable biological effects as well, most likely because of the inhibition of Notch processing.

MeSH terms

  • Administration, Oral
  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Peptides / chemistry*
  • Animals
  • Aspartic Acid Endopeptidases
  • Brain / drug effects
  • Cell Differentiation
  • Cell Division / drug effects
  • Cell Line
  • Cell Separation
  • Endopeptidases / metabolism*
  • Enzyme Inhibitors / pharmacology*
  • Flow Cytometry
  • Humans
  • Lymphocytes / metabolism
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Chemical
  • Peptides / chemistry*
  • Protein Binding
  • Receptors, Notch
  • T-Lymphocytes / cytology
  • Thymus Gland / pathology
  • Time Factors


  • Amyloid beta-Peptides
  • Enzyme Inhibitors
  • Membrane Proteins
  • Peptides
  • Receptors, Notch
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • Bace1 protein, mouse