γ-Secretase inhibitors repress thymocyte development

Brandon K. Hadland, Nancy R. Manley, Dong Ming Su, Gregory D. Longmore, Chad L. Moore, Michael S. Wolfe, Eric H. Schroeter, Raphael Kopan

Research output: Contribution to journalArticle

182 Scopus citations

Abstract

A major therapeutic target in the search for a cure to the devastating Alzheimer's disease is γ-secretase. This activity resides in a multiprotein enzyme complex responsible for the generation of Aβ42 peptides, precipitates of which are thought to cause the disease. γ-Secretase is also a critical component of the Notch signal transduction pathway; Notch signals regulate development and differentiation of adult self-renewing cells. This has led to the hypothesis that therapeutic inhibition of γ-secretase may interfere with Notch-related processes in adults, most alarmingly in hematopoiesis. Here, we show that application of γ-secretase inhibitors to fetal thymus organ cultures interferes with T cell development in a manner consistent with loss or reduction of Notch1 function. Progression from an immature CD4-/CD8- state to an intermediate CD4+/CD8+ double-positive state was repressed. Furthermore, treatment beginning later at the double-positive stage specifically inhibited CD8+ single-positive maturation but did not affect CD4+ single-positive cells. These results demonstrate that pharmacological γ-secretase inhibition recapitulates Notch1 loss in a vertebrate tissue and present a system in which rapid evaluation of γ-secrerase-targeted pharmaceuticals for their ability to inhibit Notch activity can be performed in a relevant context.

Original languageEnglish
Pages (from-to)7487-7491
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number13
DOIs
StatePublished - Jun 19 2001

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    Hadland, B. K., Manley, N. R., Su, D. M., Longmore, G. D., Moore, C. L., Wolfe, M. S., Schroeter, E. H., & Kopan, R. (2001). γ-Secretase inhibitors repress thymocyte development. Proceedings of the National Academy of Sciences of the United States of America, 98(13), 7487-7491. https://doi.org/10.1073/pnas.131202798