γ-Secretase inhibitors repress thymocyte development

摘要: A major therapeutic target in the search for a cure to devastating Alzheimer's disease is gamma-secretase. This activity resides multiprotein enzyme complex responsible generation of Abeta42 peptides, precipitates which are thought cause disease. Gamma-secretase also critical component Notch signal transduction pathway; signals regulate development and differentiation adult self-renewing cells. has led hypothesis that inhibition gamma-secretase may interfere with Notch-related processes adults, most alarmingly hematopoiesis. Here, we show application inhibitors fetal thymus organ cultures interferes T cell manner consistent loss or reduction Notch1 function. Progression from an immature CD4-/CD8- state intermediate CD4+/CD8+ double-positive was repressed. Furthermore, treatment beginning later at stage specifically inhibited CD8+ single-positive maturation but did not affect CD4+ These results demonstrate pharmacological recapitulates vertebrate tissue present system rapid evaluation gamma-secretase-targeted pharmaceuticals their ability inhibit can be performed relevant context.