Presenilin-dependent γ-secretase activity modulates thymocyte development

In neuronal cells, presenilin-dependent gamma -secretase activity cleaves amyloid precursor proteins to release A beta peptides, and also catalyzes the release of the intracellular domain of the transmembrane receptor Notch. Accumulation of aberrant A beta peptides appears to be causally related to Alzheimer`s disease. Inhibition of A beta peptide production is therefore a potential target for therapeutic intervention. Notch proteins play an important role in cell fate determination in many different organisms and at different stages of development, for example in mammalian T cell development. We therefore addressed whether structurally diverse gamma -secretase inhibitors impair Notch function by studying thymocyte development in marine fetal thymic organ cultures. Here we show that high concentrations of the most potent inhibitors blocked thymocyte development at the most immature stage. fn contrast, lower concentrations or less potent inhibitors impaired differentiation at a later stage, most notably suppressing the development of CD8 single-positive T cells. These phenotypes are consistent with an impairment of Notch signaling by gamma -secretase inhibitors and define a strict Notch dose dependence of consecutive stages during thymocyte development.