Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation
| Autor: | Eric M. Parker, Maria Pinzon-Ortiz, Hubert B. Josien, Laura W. Engstrom, Gwendolyn T. Wong, Hu-Jung J. Lee, Lili Zhang, Jay S. Fine, Frederique M. Poulet, Qi Zhang, Thomas A. Bara, Guy A. Higgins, Denise Manfra |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
medicine.medical_specialty
Time Factors Lymphocyte Cellular differentiation T cell T-Lymphocytes Administration Oral Mice Transgenic Cell Separation Thymus Gland Biochemistry Cell Line Mice In vivo Internal medicine Endopeptidases medicine Amyloid precursor protein Animals Aspartic Acid Endopeptidases Humans Lymphopoiesis Lymphocytes Enzyme Inhibitors Receptor Molecular Biology Mice Inbred C3H Amyloid beta-Peptides biology Receptors Notch Brain Membrane Proteins Cell Differentiation Cell Biology Flow Cytometry Cell biology Mice Inbred C57BL medicine.anatomical_structure Endocrinology Models Chemical biology.protein Amyloid Precursor Protein Secretases Peptides Amyloid precursor protein secretase Cell Division Protein Binding |
| Zdroj: | The Journal of biological chemistry. 279(13) |
| ISSN: | 0021-9258 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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