gamma-secretase inhibitors repress thymocyte development

A major therapeutic target in the search for a cure to the devastating Alzh eimer's disease is gamma -secretase. This activity resides in a multiprotei n enzyme complex responsible for the generation of A beta 42 peptides, prec ipitates of which are thought to cause the disease. gamma -Secretase is als o a critical component of the Notch signal transduction pathway; Notch sign als regulate development and differentiation of adult self-renewing cells. This has led to the hypothesis that therapeutic inhibition of gamma -secret ase may interfere with Notch-related processes in adults, most alarmingly i n hematopoiesis, Here, we show that application of gamma -secretase inhibit ors to fetal thymus organ cultures interferes with T cell development in a manner consistent with loss or reduction of Notch1 function. Progression fr om 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 matura tion but did not affect CD4(+) single-positive cells. These results demonst rate 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 N otch activity can be performed in a relevant context.