Chronic Treatment with the γ-Secretase Inhibitor LY-411,575 Inhibits β-Amyloid Peptide Production and Alters Lymphopoiesis and Intestinal Cell Differentiation*
By G. Wong, D. Manfra, F. Poulet, Qi Zhang, H. Josien, T. Bara, L. Engstrom, Maria C. Pinzon-Ortiz, J. Fine, Hu-Jung J. Lee and 3 more. Journal of Biological Chemistry, 2004
651 citations recorded by the source corpus.
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.
Subfields: Cellular and Molecular Neuroscience, Pharmacology, Physiology
View Paper: https://www.semanticscholar.org/paper/1d7f4dbf4c077bb443ec91488c110fe265f95cb3
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Citations in the corpus
- Protein aggregation diseases: pathogenicity and therapeutic perspectives (2010, background): “The unfortunate consequence of this is that potent γ-secretase inhibitors have serious gastrointestinal and immunological side effect”
- Modulation of notch processing by gamma-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. (2004, background): “Similar lesions caused by a potent Notch modulator , but not by a weaker Notch modulator, were observed in mice (Wong et al., 2004).”
- Alzheimer's disease: strategies for disease modification (2010, background): “Studies with several structurally different γ-secretase inhibitors at high doses have shown that inhibition of Notch1 cleavage blocks thymocyte differentiation and splenic B-cell maturation, and causes intestinal goblet-cell metaplasia in adult animal”
- Current and future treatments for Alzheimer’s disease (2013, background): “Notch-related side effects of γ-secretase inhibition (severe gastrointestinal and hemopoetic side effects) have been hampering the development of clinically useful γ-secretase inhibitors so far [Wong et al. 2004].”