γ-secretase inhibitors repress thymocyte development

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 A beta 42 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 imtermediate 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.