Chronic Treatment with the γ-Secretase Inhibitor LY-411,575 Inhibits β-Amyloid Peptide Production and Alters Lymphopoiesis and Intestinal Cell Differentiation

Inhibition of γ-secretase, one of the enzymes responsible for the cleavage of the amyloid precursor protein (APP) to produce the pathogenic β-amyloid (Aβ) peptides, is an attractive approach to the treatment of Alzheimer disease. In addition to APP, however, several other γ-secretase substrates have...

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Bibliographic Details
Published in:The Journal of biological chemistry 2004-03, Vol.279 (13), p.12876-12882
Main Authors: Wong, Gwendolyn T., Manfra, Denise, Poulet, Frederique M., Zhang, Qi, Josien, Hubert, Bara, Thomas, Engstrom, Laura, Pinzon-Ortiz, Maria, Fine, Jay S., Lee, Hu-Jung J., Zhang, Lili, Higgins, Guy A., Parker, Eric M.
Format: Article
Language:English
Subjects:
Administration, Oral
Amyloid beta-Peptides - chemistry
Amyloid Precursor Protein Secretases
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
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Summary:Inhibition of γ-secretase, one of the enzymes responsible for the cleavage of the amyloid precursor protein (APP) to produce the pathogenic β-amyloid (Aβ) peptides, is an attractive approach to the treatment of Alzheimer disease. In addition to APP, however, several other γ-secretase substrates have been identified (e.g. Notch), and altered processing of these substrates by γ-secretase inhibitors could lead to unintended biological consequences. To study the in vivo consequences of γ-secretase inhibition, the γ-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 Aβ 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 γ-secretase inhibitor. These studies show that inhibition of γ-secretase has the expected benefit of reducing Aβ in a murine model of Alzheimer disease but has potentially undesirable biological effects as well, most likely because of the inhibition of Notch processing.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M311652200