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Gamma -secretase inhibitors repress thymocyte development
B K Hadland1, N R Manley, D Su
1Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Abstract:
A major therapeutic target in the search for a cure to the devastating Alzheimer's disease is gamma-secretase. This activity resides in a multiprotein enzyme complex responsible for the generation of Abeta42 peptides, precipitates of which are thought to cause the disease. Gamma-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 gamma-secretase may interfere with Notch-related processes in adults, most alarmingly in hematopoiesis. Here, we show that application of gamma-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 gamma-secretase inhibition recapitulates Notch1 loss in a vertebrate tissue and present a system in which rapid evaluation of gamma-secretase-targeted pharmaceuticals for their ability to inhibit Notch activity can be performed in a relevant context.
Insights
Gamma-secretase inhibitors, potential Alzheimer's disease treatments, disrupt T cell development by impacting Notch1 signaling. This study shows their effects on immune cell maturation in fetal thymus organ cultures.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Gamma-secretase is a therapeutic target for Alzheimer's disease, involved in Abeta42 peptide generation.
- Gamma-secretase is crucial for Notch signaling, regulating cell development and differentiation.
- Inhibiting gamma-secretase may affect adult stem cell processes, including hematopoiesis.
Purpose of the Study:
- To investigate the impact of gamma-secretase inhibitors on T cell development.
- To determine if pharmacological gamma-secretase inhibition mimics Notch1 loss in a vertebrate model.
- To establish a system for evaluating gamma-secretase inhibitors' effects on Notch activity.
Main Methods:
- Utilized fetal thymus organ cultures treated with gamma-secretase inhibitors.
- Analyzed T cell development stages (CD4-/CD8-, CD4+/CD8+, CD4+ SP, CD8+ SP).
- Compared inhibitor effects to known Notch1 loss-of-function phenotypes.
Main Results:
- Gamma-secretase inhibition repressed progression from CD4-/CD8- to CD4+/CD8+ double-positive T cells.
- Late-stage treatment specifically inhibited CD8+ single-positive maturation.
- CD4+ single-positive cell maturation remained unaffected by late-stage treatment.
Conclusions:
- Pharmacological gamma-secretase inhibition effectively recapitulates Notch1 loss in developing T cells.
- The study provides a relevant model for assessing Notch-related side effects of gamma-secretase inhibitors.
- This research aids in evaluating the safety and efficacy of potential Alzheimer's therapeutics targeting gamma-secretase.